pyrimidinones and Neoplasms

Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity has been linked to cancer aggressiveness and poor outcomes. AZD3965, a specific MCT1 inhibitor, was tested both in vitro and in vivo, with encouraging results; a phase I clinical trial has already been undertaken. Thus, analysis of the experimental evidence using AZD3965 in different cancer types could give valuable information for its clinical use. This systematic review aimed to assess the in vivo anticancer activity of AZD3965 either alone (monotherapy) or with other interventions (combination therapy). Study search was performed in nine different databases using the keywords "AZD3965 in vivo" as search terms. The results show that AZD3965 successfully decreased tumor growth and promoted intracellular lactate accumulation, which confirmed its effectiveness, especially in combined therapy. These results support the setup of clinical trials, but other important findings, namely AZD3965 enhanced activity when given in combination with other therapies, or MCT4-induced treatment resistance, should be further considered in the clinical trial design to improve therapy response.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Management; Disease Progression; Drug Evaluation, Preclinical; Energy Metabolism; Glycolysis; Humans; Lactic Acid; Monocarboxylic Acid Transporters; Neoplasms; Pyrimidinones; Signal Transduction; Symporters; Thiophenes; Tumor Microenvironment; Warburg Effect, Oncologic; Xenograft Model Antitumor Assays

WEE1 inhibitor has been shown to potential chemotherapy or radiotherapy sensitivity in preclinical models, particularly in p53-mutated or deficient cancer cells although not exclusively. Here, we review the clinical development of WEE1 inhibitor in combination with chemotherapy or radiotherapy with concurrent chemotherapy as well as its combination with different novel agents.. Although several clinical trials have shown that WEE1 inhibitor can be safely combined with different chemotherapy agents as well as radiotherapy with concurrent chemotherapy, its clinical development has been hampered by the higher rate of grade 3 toxicities when added to standard treatments. A few clinical trials had also been conducted to test WEE1 inhibitor using TP53 mutation as a predictive biomarker. However, TP53 mutation has not been shown to be the most reliable predictive biomarker and the benefit of adding WEE1 inhibitor to chemotherapy has been modest, even in TP53 biomarker-driven studies. There are ongoing clinical trials testing WEE1 inhibitor with novel agents such as ATR and PAPR inhibitors as well as anti-PDL1 immunotherapy, which may better define the role of WEE1 inhibitor in the future if any of the novel treatment combination will show superior anti-tumor efficacy with a good safety profile compared to monotherapy and/or standard treatment.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Cell Cycle Proteins; DNA Breaks, Double-Stranded; DNA Replication; Enzyme Inhibitors; Humans; Neoplasms; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Monocarboxylic Acid Transporters; Muscle Proteins; Neoplasms; Pyrimidinones; Structure-Activity Relationship; Symporters; Thiophenes; Uracil

The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.

Topics: Antineoplastic Agents; Cell Cycle; Cell Cycle Proteins; Chemoradiotherapy; Disease Progression; DNA Repair; DNA Replication; Drug Resistance, Neoplasm; Drug Synergism; Genomic Instability; Hematologic Neoplasms; Humans; Membrane Proteins; Mitosis; Mutation; Neoplasm Proteins; Neoplasms; Oncogenes; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones; Signal Transduction; Tumor Suppressor Proteins

The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.

Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Asian People; Histiocytosis, Langerhans-Cell; Humans; Liver Neoplasms; Lung Neoplasms; MAP Kinase Kinase 1; Mice; Mutation; Neoplasms; NIH 3T3 Cells; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

Wee1 kinase controls the G2-M checkpoint. Wee1 inhibition by AZD1775 allows cells with a deregulated G1 checkpoint to progress, resulting in catastrophe and apoptosis. The challenges ahead are in the establishment of the optimum dosing schedule either alone or in combination and the identification of patients with specific biomarker profiles who benefit most.. This article provides an overview of AZD1775, based on English peer-reviewed articles on MEDLINE. The authors highlight the data from the published preclinical and clinical studies.. A majority of the current clinical trials focus on AZD1775 combined with chemotherapy or radiation. Treatment with AZD1775 was tolerated, and antitumor activity has been observed, especially in patients with advanced malignancies harboring G1 checkpoint aberrations and/or DNA damage repair defects. Thus, identification of the molecular subtypes that benefit most from the treatment with AZD1775 alone or in combination may provide a novel strategy for cancer therapy. Research is needed for devising regimens to explore AZD1775 in combination with biologically targeted agents and/or immunotherapy (low dose vs. high dose, intermittent vs. continuous, sequential vs. concurrent, etc.) for identifying potential biomarkers predictive of response and survival.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Cycle Proteins; Humans; Neoplasms; Nuclear Proteins; Patient Selection; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones

Sirtuins are a family of NAD+-dependent deacetylases (class III histone deacetylases). Seven mammalian sirtuins, SIRT1-7, are identified, as the functions and locations differ greatly. SIRT1 and SIRT2 locate in nucleus and cytoplasm, while SIRT3-5 in mitochondria. Sirtuins are not only involved in many important biological processes such as apoptosis, cellular senescence, endocrine signaling, glucose homeostasis, aging, and longevity, it can also control circadian clocks and mitochondrial biogenesis. Small molecules that can modulate the sirtuins activity have been shown to have potentials for treating many human diseases such as type II diabetes, cancer, rheumatoid arthritis, cardiovascular and other age-relating diseases. Some polyphenolic natural products such as Resveratrol, Fisetin, and Quercetin have demonstrated health benefits due to their SIRT1 activation effects. Some structurally diverse synthetic compounds, such as SRT1720, SRT1460, Selisistat (EX 527), and AGK2 were used as small molecular SIRT modulators (IC50 = 0.04-100 μM) to treat ischemic stroke, myocardial infarction, neurodegenerative diseases, cancer, aging, and obesity. In order to get better understanding of how the small molecules interact with the sirtuin, the small molecules that having SIRT inhibitory or activation effect, found by HTS or other modern medicinal chemistry techniques, are reviewed in this article.

Topics: Humans; Imidazoles; Naphthalenes; Neoplasms; Neurodegenerative Diseases; Polyphenols; Pyrimidinones; Resveratrol; Sirtuins; Small Molecule Libraries; Stilbenes; Triterpenes

Synthetic lethality refers to a lethal phenotype that results from the simultaneous disruptions of two genes, while the disruption of either gene alone is viable. Many DNA double strand break repair (DSBR) genes have synthetic lethal relationships with oncogenes and tumor suppressor genes, which can be exploited for targeted cancer therapy, an approach referred to as combination therapy. DNA double-strand breaks (DSBs) are one of the most toxic lesions to a cell and can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). HR and NHEJ genes are particularly attractive targets for cancer therapy because these genes have altered expression patterns in cancer cells when compared with normal cells and these genetic abnormalities can be targeted for selectively killing cancer cells. Here, we review recent advances in the development of small molecule inhibitors against HR and NHEJ genes to induce synthetic lethality and address the future directions and clinical relevance of this approach. © 2017 IUBMB Life, 69(12):929-937, 2017.

Topics: Benzimidazoles; Cell Cycle; Chromones; Clinical Trials as Topic; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA, Neoplasm; Humans; Indoles; Molecular Targeted Therapy; Morpholines; MRE11 Homologue Protein; Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Pyrimidinones; Recombinational DNA Repair; Synthetic Lethal Mutations; Thiones

The Small GTPase ADP-ribosylation factor 6 (Arf6) functions as the molecular switch in cellular signaling pathways by cycling between GDP-bound inactive and GTP-bound active form, which is precisely regulated by two regulators, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Numerous studies have shown that these machineries play critical roles in tumor angiogenesis/growth and cancer cell invasion/metastasis through regulating the cycling of Arf6. Here, we summarize accumulating knowledge for involvement of Arf6 GEFs/GAPs and small molecule inhibitors of Arf6 signaling/cycling in cancer progression, and discuss possible strategies for developing innovative anti-cancer drugs targeting Arf6 signaling/cycling.

Topics: Adaptor Proteins, Signal Transducing; ADP-Ribosylation Factor 6; ADP-Ribosylation Factors; Animals; Antineoplastic Agents; Cell Cycle Proteins; Chlorobenzenes; Disease Progression; Gene Expression Regulation, Neoplastic; Guanine Nucleotide Exchange Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasms; Nerve Tissue Proteins; Purines; Pyrazoles; Pyrimidinones; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Triazoles

Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.

Topics: Animals; Azetidines; Benzamides; Benzimidazoles; Diphenylamine; Genes, ras; GTP Phosphohydrolases; Humans; Membrane Proteins; Mice; Mitogen-Activated Protein Kinases; Mutation; Neoplasms; Niacinamide; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Sulfonamides

The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma).. We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years.. MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds.

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; MAP Kinase Kinase 1; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

The mitogen-activated protein kinase (MEK MAPK/ERK kinase) signaling pathways play a critical role in regulation of diverse cellular activities, including survival, differentiation, proliferation, motility, and angiogenesis. Therefore, MEK inhibition was recognized as a promising target for antineoplastic therapy. While multiple MEK inhibitors have been tested clinically only trametinib (GSK1120212), an oral MEK inhibitor which is selective for MEK1 and MEK2 has shown promising activity in several clinical trials on melanoma and colorectal cancer and it is being evaluated by the FDA for the treatment of metastatic melanoma. Mechanistically it was shown that trametinib induces cell cycle arrest in vitro. In this overview, important preclinical and clinical data for trametinib are presented including mechanism-based in vitro studies as well as findings from different clinical studies. Future clinical trial in different solid tumor entities will define the therapeutic role of this targeted therapy approach, possibly as a combination with other targeted therapies such as BRAF inhibitors.

Topics: Animals; Antineoplastic Agents; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Pyridones; Pyrimidinones

Throughout our life, long-lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self-renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG-001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI-724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Catenins; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplastic Stem Cells; Peptide Fragments; Pyrimidinones; Sialoglycoproteins; Wnt Signaling Pathway

Cancer cells usually display higher proliferation rates than normal cells. Some currently used antitumor drugs, such as vinca alkaloids and taxanes, act by targeting microtubules and inhibiting mitosis. In the last years, different mitotic regulators have been proposed as drug target candidates for antitumor therapies. In particular, inhibitors of Cdks, Chks, Aurora kinase and Polo-like kinase have been synthesized and evaluated in vitro and in animal models and some of them have reached clinical trials. However, to date, none of these inhibitors has been still approved for use in chemotherapy regimes. We will discuss here the most recent preclinical information on those new antimitotic drugs, as well as the possible molecular bases underlying their lack of clinical efficiency. Also, advances in the identification of other mitosis-related targets will be also summarized.

Topics: Antimitotic Agents; Antineoplastic Agents; Benzamides; Clinical Trials as Topic; Cyclin-Dependent Kinases; Humans; Microtubules; Mitosis; Neoplasm Proteins; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Quinazolines

Wee1, a protein kinase, regulates the G 2 checkpoint in response to DNA damage. Preclinical studies have elucidated the role of wee1 in DNA damage repair and the stabilization of replication forks, supporting the validity of wee1 inhibition as a viable therapeutic target in cancer. MK-1775, a selective and potent small-molecule inhibitor of wee1, is under clinical development as a potentiator of DNA damage caused by cytotoxic chemotherapies. We present a review of the role of wee1 in the cell cycle and DNA replication and summarize the clinical development to date of this novel class of anticancer agents.

Topics: Antineoplastic Agents; Cell Cycle Proteins; Clinical Trials as Topic; DNA Damage; DNA Repair; G2 Phase Cell Cycle Checkpoints; Humans; Neoplasms; Nuclear Proteins; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; RNA Interference

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Discovery; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Neoplasms; Oximes; Pyridones; Pyrimidinones; raf Kinases; Research; Sulfonamides; Vemurafenib

Inducing DNA damage is a well known strategy for attacking cancer, already being used for many years by the application of a variety of anti cancer drugs. Tumor cells and other rapidly dividing cells are more sensitive to DNA damage caused by DNA damaging agents compared to normal cells. While normal cells can rely on various mechanisms for DNA repair in order to protect the integrity of the genome and to promote cell survival, most tumor cells, due to genetic changes, are more challenged when it comes to repair of DNA damage. Wee 1 is a tyrosine kinase that phosphorylates CDC2 at Tyr 15 and as such plays a pivotal role in the G2 DNA damage checkpoint. The strategy of inhibition of Wee 1 by a tyrosine kinase inhibitor is exploiting the impaired options for DNA damage repair especially in cells with deregulated p53, which results in malfunction of the G1 checkpoint. Tumor cells that are unable to rely on the G1 checkpoint are more sensitive to G2 checkpoint abrogation. Administration of DNA damaging chemotherapy in combination with a Wee 1 inhibitor may therefore selectively sensitize p53 deficient cells, while normal cells are spared from toxicity. PD-166285 has been described as a novel G2 abrogator and Wee 1 inhibitor, but has also been characterized as a broad-spectrum receptor tyrosine kinase inhibitor. MK-1775 is a specific and potent inhibitor of Wee-1 and is currently under investigation in a multi-center phase I study in combination with either gemcitabine, carboplatin or cisplatin in patients with advanced solid tumors. Preliminary results show good tolerability and promising anti-cancer activity.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Proteins; DNA Damage; Drug Screening Assays, Antitumor; G2 Phase; Humans; Neoplasms; Nuclear Proteins; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Tumor Suppressor Protein p53

Purine nucleoside phosphorylase (PNP) is an important catalytic enzyme in the purine salvage pathway; its deficiency is associated with T-cell lymphopenia and with humoral deficiency. This clinical observation led to the investigation of PNP inhibitors and their possible clinical application in the management of hematologic malignancies, notably those of T-cell lineage. Forodesine is the most potent of the PNP inhibitors. Its effect appears to be linked to increased 2 -deoxyguanosine levels in plasma, which in turn is converted to 2 -deoxyguanosine triphosphate in target cells and disrupts DNA synthesis. Several preclinical studies have shown forodesine's effect against lymphocytes in vitro and in vivo, and these findings have led to several Phase I/II studies in patients with lymphoid neoplasms. Early clinical trials show that forodesine has promise as a single agent for the treatment of relapsed/refractory hematologic malignancies, and combination therapies might be warranted to improve clinical results.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Neoplasms; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; T-Lymphocytes

New anticancer agents are needed in order to overcome the resistance of cancer cells to standard chemotherapy. At present, many of the molecular events that drive the malignant transformation and progression have been identified and there is optimism that the development of agents that specifically target such events will improve treatment outcomes. Cancer cells present common alterations in components of pathways that are involved in the normal cell cycle regulation and in mechanisms of DNA damage repair. Wee1-like protein kinase is a tyrosine kinase with a key role as an inhibitory regulator of the G2/M checkpoint that precedes entry into mitosis. Abrogation of this checkpoint through Wee1 inhibition may result in increased antitumor activity of agents that cause DNA damage such as radiation therapy or some cytotoxic agents. This has been confirmed in preclinical studies and results of clinical studies evaluating a Wee1 inhibitor are awaited to establish its activity in combination with chemotherapy. Here we review the role of Wee1 tyrosine kinase in the control of the G2/M checkpoint and the effects of G2/M checkpoint abrogation through Wee1 inhibition. We present results of preclinical studies with Wee1 inhibitors and the results of the first clinical trial recently reported, evaluating MK-1775, a small-molecule inhibitor of Wee1.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Cycle Proteins; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Neoplasms; Nuclear Proteins; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones

Topics: Adenosine; Animals; Antineoplastic Agents; ATP-Binding Cassette Transporters; Biomarkers, Tumor; Cell Differentiation; Diketopiperazines; Heterocyclic Compounds, 4 or More Rings; Humans; Lapatinib; Neoplasms; Neoplastic Stem Cells; Protein Kinase Inhibitors; Pyrimidinones; Quinazolines; Signal Transduction; Triazines; Wnt Proteins

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine-salvage metabolic pathway. In humans, the loss of functional PNP results in significant T-cell-mediated immunodeficiency (and may also affect B-cell function). Forodesine is a potent PNP inhibitor that acts by elevating plasma 2'-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate, which in turn affects deoxynucleotide-triphosphate pools and induces cell death by apoptosis. BioCryst Pharmaceuticals Inc, under license from the Albert Einstein College of Medicine, is developing intravenous and oral formulations of forodesine for the potential treatment of various T-cell and B-cell lymphomas and leukemias, as well as for solid tumors; MundiPharma AG is also investigating the drug for leukemia. Forodesine effectively inhibits T-cell proliferation in vitro in the presence of dGuo. In early clinical trials, forodesine has demonstrated an acceptable safety profile and indications of biological activity. Few drug-related serious adverse events have been reported, and generally only mild-to-moderate nonhematological toxicity has been observed. Forodesine has the potential to lead the development of other novel therapies with broad-based activity for hematological malignancies; the drug may also be useful for the treatment of a wide variety of other T-cell-mediated disorders, as well as for the potential treatment for other B-cell lymphomas/leukemias.

Topics: Animals; Enzyme Inhibitors; Humans; Leukemia; Lymphoma; Neoplasms; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Structure-Activity Relationship

The main purpose of the present review article was to shed light on the different 5-fluorouracil (5-FU) prodrugs by underlining their respective pharmacological features in terms of metabolic activation, dihydropyrimidine dehydrogenase inhibition, pharmacokinetic profile and biomodulation ability. Oral fluoropyrimidines differ particularly as concerns their pharmacokinetic profile and especially in the delivery of circulating 5-FU. More clinical studies need to be performed incorporating tumour predictive markers during oral fluoropyrimidine-based treatment. The new possibilities are to achieve pharmacomodulation of oral fluoropyrimidines, notably for UFT and capecitabine, that open up the prospect of establishing significant novel treatment protocols based on drug combinations.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Capecitabine; Deoxycytidine; Fluorouracil; Humans; Neoplasms; Prodrugs; Pyrimidinones; Tegafur; Uracil

The reactive nature of species derived from oxygen, such as singlet oxygen and hydrogen peroxide, has been exploited in the clinical setting for targeting bacteria, viruses, and tumor cells by photodynamic excitation of a variety of chromophores. This modality, termed photodynamic therapy (PDT), is currently being used to treat some forms of cancer. However, the applicability of conventional PDT is limited due to the absolute dependence on simultaneous exposure of the target to the photoactive compound and light. In 1990, we demonstrated that the need for simultaneous exposure of the biological target to light and photosensitizer could be circumvented by prior exposure (activation) of the sensitizer molecule to light and its subsequent use as any other anti-cancer or anti-viral drug. By dint of the nature of the protocol, this process was termed preactivation. Since then, the generation of biologically active molecules in vitro by preactivation has been validated using a variety of chromophores, such as merocyanine 540, Photofrin II, and naphthalimide. Here we briefly review the role of reactive oxygen species in the photodynamic effect, and provide an explanation for the mechanism of preactivation. We propose that photo-oxidation not only provides a novel means for the generation of biologically active molecules, but could also explain, at least in part the mechanism of conventional PDT. It is likely that the light-dependent breakdown of the chromophore to generate novel active compounds, in addition to reactive oxygen species, also contributes to the photodynamic damage observed on simultaneous exposure of the chromophore and target tissue to light during PDT.-Pervaiz, S. Reactive oxygen-dependent production of novel photochemotherapeutic agents.

Topics: Animals; Caspases; Humans; Neoplasms; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Reactive Oxygen Species

The pros and cons of purging of either bone marrow or peripheral blood stem cell preparations for autologous transplantation for cancer has been debated strongly over the past decade. Recent data implicating the role of minimal residual disease in autografted marrow in cancer relapse have renewed interest in this question. There is a considerable body of literature supporting the possibility that photosensitizer molecules in combination with light might provide a therapeutic window permitting selective elimination of malignant stem cells while sparing those of normal lineage. Molecules of this class are known to be taken up more actively by most malignant cells, and intracellular concentrations are critical in their cytotoxic effect when they are activated by light at an appropriate wavelength. The present paper reviews the observations made over the past decade on a variety of photosensitizers and their effects on hemopoietic progenitors.

Topics: Bone Marrow Purging; Bone Marrow Transplantation; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hematoporphyrin Derivative; Humans; Indoles; Light; Neoplasms; Neoplastic Stem Cells; Organometallic Compounds; Photosensitizing Agents; Porphyrins; Pyrimidinones

Recent preclinical and clinical investigations indicate that phototherapy and photochemotherapy may have applications that go far beyond their "traditional" roles in the treatment of skin disorders, selected solid tumors, and neonatal hyperbilirubinemia. Bone marrow transplantation is one area that may benefit substantially from these new developments. This review focuses on new applications of phototherapy and photochemotherapy that pertain to the inactivation of tumor cells in autologous bone marrow grafts, the prevention and treatment of acute and chronic graft-versus-host disease, the prevention of transfusion-induced allosensitization and graft rejection, and the inactivation of pathogenic viruses and parasites in bone marrow grafts and blood products.

Topics: Animals; Antiviral Agents; Blood; Bone Marrow Purging; Bone Marrow Transplantation; Graft Rejection; Graft vs Host Disease; Humans; Immunization; Infection Control; Mice; Neoplasms; Neoplastic Stem Cells; Photochemotherapy; Photosensitizing Agents; Phototherapy; Pyrimidinones; Radiation-Sensitizing Agents; Transfusion Reaction

Topics: Animals; Cells; Coloring Agents; Humans; Leukemia; Neoplasms; Photolysis; Pyrimidinones; Radiation-Sensitizing Agents

Topics: Animals; Antineoplastic Agents; Arginase; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Deoxyribonucleases; DNA; Fluorouracil; Humans; Liver Neoplasms; Methylcholanthrene; Mice; Mutation; Neoplasms; Neoplasms, Experimental; Nucleosides; Oncogenic Viruses; Orotic Acid; Phenanthrenes; Protein Binding; Pyrimidinones; Rats; Skin Neoplasms; Thymine; Uracil

Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.. This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.. During dose escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.. AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Maximum Tolerated Dose; Neoplasms; Pyrimidinones; Thiophenes

Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed.Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2-4.1 h; mean half-life was 5-12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months.MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.

Topics: Anemia; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyrazoles; Pyrimidinones

Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).. Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on "3 + 3" design within each HD group. PK samples were collected at cycle 1 days 15-16.. Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).. RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients - 1.5 mg QD in Mod group, and 1 mg QD in Sev group.. This study was registered in the ClinicalTrials.gov website ( NCT02070549 ) on February 25, 2014. .

Topics: Adult; Aged; Female; Humans; Liver Diseases; Male; Middle Aged; Neoplasms; Pyridones; Pyrimidinones

Lay abstract This study aims to report the long-term outcome of intra-ocular inflammation (uveitis) associated with cancer immunotherapy (CIT). Serial patients complaining of blurred vision and painful eyes showed intra-ocular inflammation that was related to CIT, after infectious, inflammatory and tumoral causes of uveitis have been ruled out. The length of follow-up was more than 12 months for most patients. Eight serial patients treated with rituximab (anti-CD20), nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4), vemurafenib and dabrafenib (anti-BRAF), trametinib (anti-MEK) and ibritunib showed intra-ocular inflammation with hypopion (one patient), macular edema (five patients) and choroiditis (two patients). Various regimens of corticosteroid therapy showed a favorable ophthalmological outcome, whether the CIT was continuing or suspended. Local corticosteroid injections in combination with CIT could be suggested as a first-line treatment. This could help to preserve the quality of life without threatening the vital prognosis.

Topics: Adrenal Cortex Hormones; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Middle Aged; Neoplasms; Nivolumab; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Rituximab; Uveitis; Vemurafenib

The Wee1 kinase inhibitor adavosertib abrogates cell-cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase II dose (RPh2D). Here, we report results for once-daily adavosertib.. A 3 + 3 dose-escalation design was used, with adavosertib given once daily on days 1 to 5 and 8 to 12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15-phosphorylated Cdk1/2 (pY15-Cdk), were assessed in paired tumor biopsies. Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers.. Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematologic; dose-limiting toxicities were grade 4 hematologic toxicity and grade 3 fatigue. The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses: four ovarian, two endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in four of eight patients, suggesting target rebound during the day 5 to 8 dosing break. One patient who progressed rapidly had a tumor. We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including two with baseline

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Cycle Proteins; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Neoplasms; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones; Treatment Outcome

This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm).. Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway.. Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%;. Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Carboplatin; DNA, Neoplasm; Double-Blind Method; Everolimus; Female; Gene Expression Profiling; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Neoplasms; Pyrazoles; Pyridones; Pyrimidinones; Temozolomide; Young Adult

Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with. The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with prespecified fusions and non-V600 mutations in. Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a. Trametinib did not show promising clinical activity in patients with tumors harboring non-V600

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Lymphoma; Male; Middle Aged; Mutation; National Cancer Institute (U.S.); Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate; Treatment Outcome; United States

The WEE1 inhibitor adavosertib (AZD1775) has been investigated in Western patients.. This open-label Phase Ib study (NCT02341456) investigated the safety, pharmacokinetics, and clinical activity of adavosertib in combination with carboplatin alone or paclitaxel plus carboplatin in Asian patients with advanced solid tumors and defined the recommended Phase II dose.. Adavosertib 175 mg bid for 2.5 days with carboplatin alone or paclitaxel plus carboplatin was considered tolerable. Two patients receiving adavosertib 225 mg bid in combination with paclitaxel plus carboplatin experienced dose-limiting toxicities (grade 4 sepsis; grade 5 acute respiratory distress syndrome); this regimen was not considered tolerable. Grade ≥ 3 adverse events reported most commonly in any cohort included: anemia; decreased white blood cell count; decreased neutrophil count; neutropenia; decreased platelet count; thrombocytopenia; and febrile neutropenia. Exposure to adavosertib, as determined by pharmacokinetic analysis, in Asian patients was higher than that previously seen in Western patients. A partial response occurred in 2/12 evaluable patients (16.7%) at the recommended Phase II dose.. Adavosertib 175 mg bid for 2.5 days was chosen as the recommended Phase II dose in combination with paclitaxel and carboplatin in Asian patients.

Topics: Asian People; Cohort Studies; Enzyme Inhibitors; Female; Humans; Male; Neoplasms; Pyrazoles; Pyrimidinones

To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors.. In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states.. Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (C. A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Biological Availability; Cell Cycle Proteins; Cross-Over Studies; Diet, High-Fat; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones

Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy.. This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed.. Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks).. Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

Topics: Aged; Aminopyridines; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Focal Adhesion Protein-Tyrosine Kinases; Humans; Hydroxamic Acids; Male; Mesothelioma; Middle Aged; Neoplasms; Progression-Free Survival; Pyridones; Pyrimidinones

Trametinib is a reversible, selective inhibitor of the mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and 2 (MEK2). Cardiotoxicity (congestive heart failure, decreased heart rate, left ventricular dysfunction, and hypertension) related to trametinib is an infrequent, but serious, adverse event (AE). Prolongation of the QT interval increases the risk of life-threatening cardiac arrhythmia. Thus, the risk of trametinib inducing QT prolongation at putative supratherapeutic exposure was evaluated.. Eligible patients with solid tumours received placebo on day 1, once-daily trametinib 2-mg doses on days 2-14, and a single trametinib 3-mg dose on day 15 to achieve supratherapeutic dosing for QTc measurement. Electrocardiogram was assessed by 12-lead ambulatory 24-h Holter monitoring pre-dose, and on day 1 and day 15. Pharmacokinetic (PK) and pharmacodynamics (PD) parameters were measured.. Thirty-two of 35 patients completed the study. There was no effect of trametinib when compared with time-matched placebo on the change from baseline in QTcF, QTcB, or QTcI interval. Mean AUC0-24 and C max following trametinib 2-mg repeat doses were 364 ng.h/mL and 22.9 ng/mL, respectively; the corresponding values for the 3-mg dose were 454 ng.h/mL and 29.2 ng/mL. Median T max was approximately 2 h for both doses. Statistical analysis and PK/PD modelling showed no significant relationship between QTcF interval and trametinib plasma concentrations. AEs were consistent with those reported previously. No electrocardiogram abnormalities were reported as AEs.. The results of this study suggest trametinib has no significant effect on QT prolongation at supratherapeutic exposure.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Area Under Curve; Cardiotoxicity; Electrocardiography; Electrocardiography, Ambulatory; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Models, Biological; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Single-Blind Method; Young Adult

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Topics: Adult; Aged; Biomarkers, Tumor; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; MAP Kinase Kinase 1; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Prognosis; Protein Kinase Inhibitors; Pyridazines; Pyridones; Pyrimidinones; Quinolines; Sulfonamides; Survival Rate; Tissue Distribution; TOR Serine-Threonine Kinases; Young Adult

This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity.. A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle.. Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%).. This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Everolimus; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib.. Eligibility criteria were advanced solid tumors, 18 years or older, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy. Clinical safety parameters and response were evaluated and analyzed.. Twenty patients were enrolled. Dose-limiting toxicities (Grade 2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5 mg trametinib/50 mg afuresertib once daily continuously), exceeding the MTD. Subsequent de-escalation cohorts (1.5 mg/25 mg or 1.0 mg/50 mg trametinib/afuresertib) were defined as MTDs for continuous dosing. Intermittent dosing schedule [1.5 mg trametinib (continuous)/50 mg afuresertib (Days 1-10 every 28 days)] was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (≥10 % of all patients) included: diarrhea (60 %), dermatitis acneiform (55 %), maculo-papular rash (45 %), fatigue (30 %), dry skin (25 %), nausea (25 %), dyspnea (20 %), and vomiting (20 %). One partial response (BRAF wild-type melanoma) was reported; four patients had stable disease as best response.. Continuous daily dosing of trametinib/afuresertib combination was poorly tolerated. Evaluation of intermittent dose schedule showed greater tolerability. Given the interest in combination treatment regimens of MAPK and PI3K/AKT pathway inhibitors, further study of intermittent dose schedule or combination of trametinib with more selective inhibitors may be warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Early Termination of Clinical Trials; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Multiple Myeloma; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones; Thiophenes; Tumor Burden

MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.. This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer.. Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.. At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Morpholines; Neoplasms; Pyridones; Pyrimidinones

Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies.. AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3 + 3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD.. Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in γH2AX levels (three of five paired biopsies) were demonstrated.. This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Cell Cycle Proteins; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasms; Nuclear Proteins; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Young Adult

Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results.. In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)).. In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2).. Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.).

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Asian People; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gemcitabine; Humans; Japan; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pancreatic Neoplasms; Pyridones; Pyrimidinones

Trametinib (Mekinist®) is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) approved in the United States as a single agent and in combination with dabrafenib (Tafinlar®) for treatment of patients with unresectable or metastatic melanoma with a positive BRAF V600E/V600K mutation for which a pediatric oral solution formulation is being developed. This open-label, two-period, two-treatment, randomized, crossover study assessed the relative bioavailability of the trametinib pediatric oral solution compared to the tablet formulation after a single-dose administration to adult patients with solid tumors. Primary pharmacokinetic endpoints derived from standard non-compartmental methods were AUC0-inf , AUC0-t , and Cmax . As expected, Cmax was higher and Tmax earlier for the pediatric oral solution compared to the tablet formulation. Administration of the trametinib pediatric oral solution resulted in a 12%, 10%, 18%, and 71% higher AUC0-inf , AUC0-last , AUC0-24 , and Cmax , respectively, as compared to the tablet formulation. Safety results were aligned with the known safety profile of trametinib. No serious or non-serious adverse events resulted in study drug withdrawal. Palatability of the pediatric oral solution was evaluated and found to be acceptable to most adult patients, but may differ in the pediatric population.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Biological Availability; Cross-Over Studies; Drug Compounding; Female; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Neoplasms; Patient Satisfaction; Pharmaceutical Solutions; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tablets; Taste; United States

The aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2 mg oral dose of trametinib. Trametinib is an orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.. A microtracer study approach, in which a 5 μg radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2 mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously.. The least-squares mean (90% confidence interval) absolute bioavailability of trametinib (2 mg tablet) was 72.3% (50.0%, 104.6%). Median tmax after oral administration was 1.5 h and the geometric mean terminal half-life was 11 days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21 l h(-1) and 976 l, respectively, resulting in a terminal elimination half-life of 11 days.. Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.

Topics: Administration, Intravenous; Administration, Oral; Antineoplastic Agents; Biological Availability; Female; Half-Life; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tissue Distribution

This phase 1b study determined the safety, tolerability, and recommended phase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. Secondary objectives included assessment of clinical activity and steady-state pharmacokinetics.. Adults with advanced solid tumours, adequate organ function and Eastern Co-operative Oncology Group performance status (ECOG PS) ⩽ 1 were eligible. Once-daily oral trametinib (1mg, 2mg, 2.5mg) was escalated in a 3+3 design with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 of 28-day cycles). During expansion, trametinib 2mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 pre-dose and 1, 2, 4 and 6h post-dose; tumour assessments were repeated every two cycles.. Between 8/2009 and 11/2010, 31 patients (pancreas = 11, breast = 6, non-small cell lung cancer (NSCLC) = 4, other = 10) were treated. Dose-limiting toxicities (DLTs) occurred in each cohort, and included febrile neutropenia, transaminase elevation and uveitis. The RP2D was declared as trametinib 2mg daily with standard gemcitabine dosing. Common grade 3/4 toxicities at the RP2D included: neutropenia (38%), thrombocytopenia (19%) and transaminase elevation (14%). Of 10 patients with measurable pancreatic cancer, three partial responses (30%) were documented; two additional patients achieved objective responses (breast, complete response (CR); salivary glands, partial response (PR)). Pharmacokinetics suggested no change in exposures of either drug in combination.. Administration of trametinib at its full monotherapy dose of 2mg daily in combination with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 every 28 days) was feasible. Though most toxicities were manageable, the addition of trametinib may increase gemcitabine-associated myelosuppression. Future studies of this combination will require monitoring to maintain dose and schedule.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Pyridones; Pyrimidinones; Thrombocytopenia; Treatment Outcome

The aim of this study was to estimate the effect of a high-fat, high-calorie meal on the single-dose pharmacokinetics (PK) of trametinib, a MEK inhibitor. The design of this 2 treatment, 2 period crossover, incomplete wash-out study was influenced by the subject population, long half-life and PK variability; 24 subjects were randomized to a single, oral 2 mg trametinib dose administered in a fed/fasted state, followed by 7 days of serial PK sampling. Period 2 PK parameters were adjusted based on residual Period 1 concentrations. Geometric least square mean ratios of fed:fasted were 0.30, 0.76, and 0.90 for corrected maximum concentration (C(max)), area under concentration-time curve from time 0 to last quantifiable sample (AUC(0-last)) and AUC from time 0 extrapolated to infinity (AUC(0-α)), respectively. Median half-life was 6.3 and 5.3 days for fed and fasted regimens, respectively. Uncorrected PK parameters were consistent with these results. Food delayed absorption and had a mean difference in time of maximum concentration (t(max)) of 3.9 hours. Both oral trametinib doses were well-tolerated. Single-dose trametinib administration with food decreased the rate and, to a lesser degree, the extent of absorption, supporting the recommendation to administer trametinib 1 hour before or 2 hours after a meal.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Cross-Over Studies; Diet, High-Fat; Fasting; Female; Food-Drug Interactions; Half-Life; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma.. In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/- PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD.. 29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs).. AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs.

Topics: Adult; Aged; Benzamides; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kinesins; Lymphoma, B-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prognosis; Pyrimidinones; Tissue Distribution

Inhibition of kinesin spindle protein or Eg5 causes the formation of monoastral mitotic spindles, which leads to cell death. AZD4877 is a specific, potent inhibitor of Eg5.. This was a Phase I, open-label, two-part study to evaluate the maximum tolerated dose (MTD) and safety and tolerability of AZD4877 in patients with advanced solid malignancies. In part A, the MTD of AZD4877, administered as three weekly 1-h intravenous (iv) infusions in a 28-day schedule, was determined by evaluating dose-limiting toxicity (DLT). In part B, the safety, tolerability, and pharmacokinetic profile of AZD4877 at the MTD were evaluated.. In part A, 29 patients received at least one dose of AZD4877 (5 mg, n = 4; 7.5 mg, n = 4; 10 mg, n = 3; 15 mg, n = 3; 20 mg, n = 3; 30 mg, n = 6; 36 mg, n = 3; 45 mg, n = 3). The MTD was defined as 30 mg, with the primary DLT being neutropenia. Although exposures appeared to be similar at the AZD4877 20 and 30 mg doses, dose reductions and omissions were higher in the 30-mg cohort; therefore, an intermediate dose, 25 mg, was evaluated in part B (n = 14). In part B, neutropenia remained the most commonly reported causally related adverse event. Exposure to AZD4877 was approximately dose proportional. Severity of neutropenia was related to exposure.. The MTD of AZD4877 given as a 1-h iv infusion on days 1, 8, and 15 of a 28-day cycle was 30 mg. At the selected 25 mg dose, AZD4877 had an acceptable safety profile.

Topics: Adult; Aged; Aged, 80 and over; Benzamides; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Kinesins; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Pyrimidinones; Severity of Illness Index

Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours.. We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622.. We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded.. The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination.. GlaxoSmithKline.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Biopsy; Drug Administration Schedule; Drug Monitoring; Female; Half-Life; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Metabolic Clearance Rate; Middle Aged; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; United States; Young Adult

Recent preclinical and clinical investigations indicate that phototherapy and photochemotherapy may have applications that go far beyond their "traditional" roles in the treatment of skin disorders, selected solid tumors, and neonatal hyperbilirubinemia. Bone marrow transplantation is one area that may benefit substantially from these new developments. This review focuses on new applications of phototherapy and photochemotherapy that pertain to the inactivation of tumor cells in autologous bone marrow grafts, the prevention and treatment of acute and chronic graft-versus-host disease, the prevention of transfusion-induced allosensitization and graft rejection, and the inactivation of pathogenic viruses and parasites in bone marrow grafts and blood products.

Topics: Animals; Antiviral Agents; Blood; Bone Marrow Purging; Bone Marrow Transplantation; Graft Rejection; Graft vs Host Disease; Humans; Immunization; Infection Control; Mice; Neoplasms; Neoplastic Stem Cells; Photochemotherapy; Photosensitizing Agents; Phototherapy; Pyrimidinones; Radiation-Sensitizing Agents; Transfusion Reaction

Adavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors.. Eligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1-2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (C. Twenty-one patients received adavosertib. Concentration-QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of C. Adavosertib does not have a clinically important effect on QTc prolongation.. GOV: NCT03333824.

Topics: Antineoplastic Agents; Electrocardiography; Humans; Neoplasms; Pyrazoles; Pyrimidinones

Topics: Fever; Humans; Imidazoles; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Fever; Humans; Imidazoles; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

This phase 1 postapproval study assessed the effect of the mitogen-activated protein kinase kinase enzyme 1/enzyme 2 inhibitor trametinib (2 mg once daily, repeat dosing) on the pharmacokinetics of combined oral contraceptives (COCs) containing norethindrone (NE; 1 mg daily) and ethinyl estradiol (EE; 0.035 mg daily) in 19 female patients with solid tumors. Compared with NE/EE administered without trametinib, NE/EE administered with steady-state trametinib was associated with a clinically nonrelevant 20% increase in NE exposure (area under the curve [AUC]) and no effect on EE exposure (geometric mean ratio [geo-mean] of NE/EE + trametinib to NE/EE [90%CI]: NE AUC calculated to the end of a dosing interval at steady-state [AUC

Topics: Contraceptives, Oral, Combined; Ethinyl Estradiol; Female; Humans; Male; Neoplasms; Norethindrone; Pyridones; Pyrimidinones

Despite notable advances in utilising PARP inhibitor monotherapy, many cancers are not PARP inhibitor-sensitive or develop treatment resistance. In this work, we show that the two structurally-related sesquiterpene lactones, a 2-bromobenzyloxy derivative of dehydrosantonin (BdS) and alantolactone (ATL) sensitise p53 wildtype, homologous recombination-proficient cancer cells to low-dose treatment with the PARP inhibitor, olaparib. Exposure to combination treatments of olaparib with BdS or ATL induces cell-cycle changes, chromosomal instability, as well as considerable increases in nuclear area. Mechanistically, we uncover that mitotic errors likely depend on oxidative stress elicited by the electrophilic lactone warheads and olaparib-mediated PARP-trapping, culminating in replication stress. Combination treatments exhibit moderately synergistic effects on cell survival, probably attenuated by a p53-mediated, protective cell-cycle arrest in the G2 cell-cycle phase. Indeed, using a WEE1 inhibitor, AZD1775, to inhibit the G2/M cell-cycle checkpoint further decreased cell survival. Around half of all cancers diagnosed retain p53 functionality, and this proportion could be expected to increase with improved diagnostic approaches in the clinic. Utilising sublethal oxidative stress to sensitise p53 wildtype, homologous recombination-proficient cancer cells to low-dose PARP-trapping could therefore serve as the basis for future research into the treatment of cancers currently refractory to PARP inhibition.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromosomal Instability; Dose-Response Relationship, Drug; Drug Synergism; Humans; Lactones; Neoplasms; Oxidative Stress; Phthalazines; Piperazines; Pyrazoles; Pyrimidinones; Sesquiterpenes; Sesquiterpenes, Eudesmane; Tumor Suppressor Protein p53

Topics: Child; Chromosome Deletion; Chromosomes, Human, Pair 7; Humans; Neoplasms; Pyridones; Pyrimidinones

Topics: Amides; Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrimidinones

Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non-small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials.. Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively).. Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy.. Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption.. ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908).

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fever; Humans; Imidazoles; Male; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

In this issue of

Topics: Adult; Cell Cycle Proteins; Child; CRISPR-Cas Systems; Humans; Neoplasms; Nuclear Proteins; Protein-Tyrosine Kinases; Pyrimidinones; X-linked Nuclear Protein

Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate. Information-rich assays, such as gene-expression profiling, have generally not permitted efficient profiling of a given perturbation across multiple cellular contexts. Here, we develop MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines. We combine it with Cell Hashing to further multiplex additional experimental conditions, such as post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and enable prediction of long-term cell viability from short-term transcriptional responses to treatment.

Topics: Antineoplastic Agents; Base Sequence; Cell Line, Tumor; Cell Survival; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Models, Statistical; Neoplasms; Polymorphism, Single Nucleotide; Pyridones; Pyrimidinones; Single-Cell Analysis

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition

Topics: Adolescent; Adult; Animals; Benzamides; Cell Proliferation; Cell-Free Nucleic Acids; Child; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Heterografts; Humans; Imidazoles; Indazoles; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Neoplasms; Oncogene Proteins, Fusion; Oximes; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Receptor, trkA; Young Adult

The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conformational restriction approach to explore a novel chemical space for the generation of TORKi. Structure-activity relationship (SAR) studies led to the identification of compound

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Dogs; Drug Design; Humans; Inhibitory Concentration 50; Kinetics; Male; Mice; Molecular Conformation; Neoplasms; Oxazines; Protein Kinase Inhibitors; Pyrimidinones; Pyrroles; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; TOR Serine-Threonine Kinases

New 2,3-disubstituted thieno[2,3-

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cells, Cultured; Drug Screening Assays, Antitumor; Humans; Neoplasms; Pyrimidinones

Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were (i) systemic plasticity, (ii) change in population abundance, (iii) change in signature population features, and (iv) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor-resident DN T cells were abnormal and phenotypically distinct from those found in nonmalignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types.

Topics: Adenoids; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Female; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Middle Aged; Monitoring, Immunologic; Neoplasms; Oximes; Palatine Tonsil; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; T-Lymphocytes

KRAS mutation is the most common type of mutation in human cancers. However, the direct pharmacological inhibition of KRAS has not been clinically successful. Trametinib (GSK1120212, Tram), a newer MEK inhibitor, inhibits RAS signaling through mitogen-activated protein kinase (MAPK) cascade suppression. The effectiveness of Tram in clinical practice is limited in KRAS mutant tumors compared to that in BRAF mutant tumors. Here, we found that Tram treatment provoked feedback activation of upstream RAS, thus causing an induction of phosphorylated MEK (pMEK) and phosphorylated ERK (pERK) rebound in KRAS mutant tumors. This failure of persistent ERK inhibition led to drug resistance. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, disrupts the biological activity of RAS by inhibiting its isoprenylation. Surprisingly, ZA overcame Tram resistance, and augmented antitumor activity was observed in KRAS mutant tumors both in vitro and in vivo. Furthermore, ZA enhanced the effect of Tram partially through the mevalonate pathway. In summary, the combination of the two FDA-approved drugs Tram and ZA may represent a novel therapeutic strategy for the treatment of KRAS mutant cancers.

Topics: A549 Cells; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; HCT116 Cells; HT29 Cells; Humans; Mevalonic Acid; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Prenylation; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays; Zoledronic Acid

Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K+) channels and apical membrane chloride (Cl-) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl- secretion was Ca2+ and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K+ channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K+ and apical Cl- channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K+ channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K+ and Cl- channel activation and support the therapeutic efficacy of channel inhibitors.

Topics: Acetamides; Afatinib; Animals; Cell Membrane Permeability; Clotrimazole; Colon; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Disease Models, Animal; Epithelial Cells; ErbB Receptors; Female; Humans; Intestinal Mucosa; Neoplasms; Oxazines; Potassium Channel Blockers; Potassium Channels; Protein Kinase Inhibitors; Pyrimidinones; Pyrroles; Rats; Trityl Compounds

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.

Topics: Administration, Oral; Allosteric Regulation; Allosteric Site; Aminopyridines; Animals; Antineoplastic Agents; Cell Line, Tumor; Crystallography, X-Ray; Enzyme Inhibitors; Female; Humans; Male; Mice, Inbred C57BL; Molecular Structure; Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidinones; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Cell Cycle Proteins; Cell Survival; Checkpoint Kinase 1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; DNA Damage; HCT116 Cells; Humans; Neoplasms; Phosphorylation; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones; RNA, Small Interfering; S Phase Cell Cycle Checkpoints; Transfection

Aberrant activation of the PI3K pathway is a common alteration in human cancers. Therapeutic intervention targeting the PI3K pathway has achieved limited success due to the intricate balance of its different components and isoforms. Here, we systematically investigated the genomic and transcriptomic signatures associated with response to KIN-193, a compound specifically targeting the p110β isoform. By integrating genomic, transcriptomic, and drug response profiles from the Genomics of Drug Sensitivity in Cancer database, we identified mutational and transcriptomic signatures associated with KIN-193 and further created statistical models to predict the treatment effect of KIN-193 in cell lines, which may eventually be clinically valuable. These predictions were validated by analysis of the external Cancer Cell Line Encyclopedia dataset. These results may assist precise therapeutic intervention targeting the PI3K pathway. SIGNIFICANCE: These findings provide new insights into molecular signatures associated with sensitivity of the p110β inhibitor KIN-193, which may provide a useful guide for developing precise treatment methods for cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Class Ia Phosphatidylinositol 3-Kinase; Databases, Factual; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Machine Learning; Models, Statistical; Mutation; Neoplasms; ortho-Aminobenzoates; Phosphoinositide-3 Kinase Inhibitors; PTEN Phosphohydrolase; Pyrimidinones; Reproducibility of Results; Treatment Outcome

Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway. MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. In primary human fibroblasts, activated AKT suppresses MRN complex expression to escalate RAS-induced DNA damage and thereby reinforce oncogene-induced senescence. Taken together, our data demonstrate that deregulation of the PI3K-AKT/ mTORC1/ p70S6K pathways, an event frequently observed in cancer, exert profound effects on genome stability via MRE11 with potential implications for tumour initiation and therapy.

Topics: DNA Damage; Down-Regulation; Fibroblasts; Gene Expression Regulation, Neoplastic; Genomic Instability; HCT116 Cells; Humans; Mechanistic Target of Rapamycin Complex 1; MRE11 Homologue Protein; Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyrimidinones; Radiation Tolerance; Recombinational DNA Repair; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Small Interfering; Signal Transduction; Thiones; X-Rays

Phosphoinositide 3-kinase (PI3K) β is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kβ-selective inhibitor (clinicaltrials.gov identifier NCT01673737).. Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions.. Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m. SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24. © 2017 American Cancer Society.

Topics: Adult; Aged; Bayes Theorem; Female; Humans; Indoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Pyrimidinones

During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK

Topics: Animals; Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Glycogen Synthase Kinase 3 beta; Humans; Mice; Molecular Dynamics Simulation; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt; Pyrimidinones; Stereoisomerism; Structure-Activity Relationship; Transplantation, Heterologous

Oncogenic KRAS mutations occur frequently in solid tumours, but no clinically applicable targeted strategy is yet available for treating human cancers with mutant KRAS. Here we aimed to identify a strategy for the treatment of KRAS-driven cancers.. Cell viability and colony forming assays were used to assess the in vitro effect of dasatinib and trametinib as single agents or in combination. Western blot was used to analyse the phosphorylated protein and total protein levels. Xenograft models were used to evaluate the in vivo effect of drug combination on KRAS-driven tumour growth.. Here, we report the discovery of a synergistic interaction between dasatinib (ABL and SRC family kinase inhibitor) and the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib in KRAS-mutant cancer cells. We demonstrated that dasatinib enhanced the antitumour effect of trametinib against the KRAS-mutant cancer models both in vitro and in vivo, and the combination resulted in a significant reduction of cytoplasmic and nucleic TAZ protein level, and therefore decreased downstream protein levels of YAP/TAZ signalling pathway. Furthermore, direct knockdown of TAZ by small interfering RNA was able to increase the sensitivity of KRAS-mutant cells to trametinib treatment.. These results indicate that dasatinib enhances the antitumour activity of MEK inhibitor through inhibition of TAZ activity and identify dasatinib and trametinib combination as a potential strategy for the treatment of KRAS-driven cancers.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dasatinib; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasms; Phosphoproteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; RNA, Small Interfering; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Treatment Outcome; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Neoplasms; Pyrimidinones; TOR Serine-Threonine Kinases

DNA damage response plays an eminent role in patients' response to conventional chemotherapy and radiotherapy. Its inhibition is of great interest as it can overcome cancer cell resistance and reduce the effective doses of DNA damaging agents. Results & methodology: We have focused our research on phosphatidylinositol 3-kinase-related kinases and prepared 35 novel compounds through a scaffold hopping approach. The newly synthesized inhibitors were tested on a panel of nine cancer and one healthy cell lines alone and in combination with appropriate doses of doxorubicin.. Five novel compounds 4f, 10b, 15g, 7e and 15f in combination with doxorubicin showed significant antiproliferative effect on seven cancer cell lines while not affecting the cell growth alone.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Humans; Neoplasms; Purinones; Pyrimidinones; Pyrroles

This observational study investigates the effectiveness and safety of dabrafenib/trametinib combination in patients with metastatic melanoma.. Seventy-six patients treated with dabrafenib/trametinib (150 mg twice daily/2 mg once daily) were included.. Median progression-free survival was 9 months (95% CI: 7-11) and median overall survival was 14 months (11-16); disease control rate was 72%. Nine patients (12%) experienced a complete response. Of these, seven presented one metastatic site, none had lung or CNS metastasis, and none had elevated baseline lactate dehydrogenase (LDH) levels. Overall, subgroup analysis for patients with adverse prognostic features led to similar results. No new safety signals were reported.. Dabrafenib/trametinib combination can be effective and well-tolerated also in a heterogeneous 'real life' population comprising patients with adverse prognostic features.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Imidazoles; Italy; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Oximes; Prognosis; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

Inhibition of epidermal growth factor receptor (EGFR) signaling by small molecule kinase inhibitors and monoclonal antibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here, we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling. This change in downstream signaling leads to apoptosis and growth inhibition in response to epidermal growth factor (EGF) in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to the nuclear pool of STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death, without affecting EGFR:ERK1/2 signaling. Pharmacologic blockade of ERK1/2 signaling through the use of the allosteric MEK1/2 inhibitor, trametinib, dramatically biases downstream EGFR signaling toward a STAT1-dominated event, resulting in enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, combined administration of trametinib and EGF also facilitated an apoptotic switch in EGFR-transformed primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental distinction for EGFR function in metastatic BC. Furthermore, the data demonstrate that pharmacological biasing of EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Endocytosis; Epidermal Growth Factor; ErbB Receptors; Gefitinib; Humans; Ligands; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mice; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; STAT1 Transcription Factor

To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors.. A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT).. Single-center, retrospective cohort study.. Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point.. Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation.. The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001).. The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azetidines; Benzimidazoles; Central Serous Chorioretinopathy; Female; Fluorescein Angiography; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retinal Detachment; Retrospective Studies; Subretinal Fluid; Tomography, Optical Coherence; Visual Acuity; Young Adult

In this issue of Cell Chemical Biology,Benoit et al. (2017) report the selective targeting of cancer stem cells (CSCs) by the ICG-001/CWP family of molecules. Their findings reveal that Sam68 is a transcriptional modulator uniquely required for the dysregulated Wnt/β-catenin signaling in CSCs over healthy stem cells.

Topics: Antineoplastic Agents; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Humans; Neoplasms; Neoplastic Stem Cells; Pyrimidinones; Signal Transduction; Wnt Proteins; Wnt Signaling Pathway

Topics: A549 Cells; Animals; Cell Cycle Proteins; Cyclin-Dependent Kinase 2; DNA Breaks, Single-Stranded; DNA-Binding Proteins; DNA-Directed DNA Polymerase; DNA, Neoplasm; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Humans; M Phase Cell Cycle Checkpoints; Mice; Neoplasms; Nuclear Proteins; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Signal Transduction; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.

Topics: Animals; Bortezomib; Camptothecin; Cell Cycle Proteins; Child; Clone Cells; Drug Therapy, Combination; Epigenesis, Genetic; Female; Heterografts; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Indoles; Irinotecan; Mice; Neoplasms; Nuclear Proteins; Panobinostat; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Rhabdomyosarcoma; Vincristine; Xenograft Model Antitumor Assays

Claisen-Schmidt condensation of 2,3,4,9-tetrahydro-1H-carbazol-1-one with 3-bromo-4-methoxy benzaldehyde afforded the 2-(3'-bromo-4'-methoxybenzylidene)-2,3,4,9-tetrahydro-1H-carbazol-1-one 3. Compound 3 was allowed to react with different organic reactants, hydroxylamine hydrochloride, malononitrile and guanidine nitrate through condensation cum cycloaddition reactions to afford a series of the respective novel hetero annulated carbazoles such as isoxazolo-, pyrido- and pyrimido carbazoles. The structures of the compounds were established by FT-IR,

Topics: Antineoplastic Agents; Carbazoles; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Isoxazoles; Molecular Structure; Neoplasms; Pyridones; Pyrimidines; Pyrimidinones; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Tumor Cells, Cultured

Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5' fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall-cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs. nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs. nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs. nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Child, Preschool; Female; Gene Expression Profiling; Humans; Infant; Male; Middle Aged; Molecular Targeted Therapy; Neoplasms; Niacinamide; Oncogene Proteins, Fusion; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sorafenib; Transcriptome; Treatment Outcome; Young Adult

DNA damage activates Checkpoint kinase 1 (Chk1) to halt cell cycle progression thereby preventing further DNA replication and mitosis until the damage has been repaired. Consequently, Chk1 inhibitors have emerged as promising anticancer therapeutics in combination with DNA damaging drugs, but their single agent activity also provides a novel approach that may be particularly effective in a subset of patients. From analysis of a large panel of cell lines, we demonstrate that 15% are very sensitive to the Chk1 inhibitor MK-8776. Upon inhibition of Chk1, sensitive cells rapidly accumulate DNA double-strand breaks in S phase in a CDK2- and cyclin A-dependent manner. In contrast, resistant cells can continue to grow for at least 7 days despite continued inhibition of Chk1. Resistance can be circumvented by inhibiting Wee1 kinase and thereby directly activating CDK2. Hence, sensitivity to Chk1 inhibition is regulated upstream of CDK2 and correlates with accumulation of CDC25A. We conclude that cells poorly tolerate CDK2 activity in S phase and that a major function of Chk1 is to ensure it remains inactive. Indeed, inhibitors of CDK1 and CDK2 arrest cells in G1 or G2, respectively, but do not prevent progression through S phase demonstrating that neither kinase is required for S phase progression. Inappropriate activation of CDK2 in S phase underlies the sensitivity of a subset of cell lines to Chk1 inhibitors, and this may provide a novel therapeutic opportunity for appropriately stratified patients.

Topics: Antineoplastic Agents; cdc25 Phosphatases; Cell Line, Tumor; Checkpoint Kinase 1; Cyclin A; Cyclin E; Cyclin-Dependent Kinase 2; DNA Breaks, Double-Stranded; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Activation; Histones; Humans; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrimidinones; S Phase Cell Cycle Checkpoints; Signal Transduction; Time Factors

The intracellular PI3K-AKT-mTOR pathway is involved in regulation of numerous important cell processes including cell growth, differentiation, and metabolism. The PI3Kα isoform has received particular attention as a novel molecular target in gene therapy, since this isoform plays critical roles in tumor progression and tumor blood flow and angiogenesis. However, the role of PI3Kα and other class I isoforms, i.e. PI3Kβ, γ, δ, in the regulation of vascular tone and regional blood flow are largely unknown. We used novel isoform-specific PI3K inhibitors and mice deficient in both PI3Kγ and PI3Kδ (Pik3cg(-/-)/Pik3cd(-/-)) to define the putative contribution of PI3K isoform(s) to arterial vasoconstriction. Wire myography was used to measure isometric contractions of isolated murine mesenteric arterial rings. Phenylephrine-dependent contractions were inhibited by the pan PI3K inhibitors wortmannin (100 nM) and LY294002 (10 µM). These vasoconstrictions were also inhibited by the PI3Kα isoform inhibitors A66 (10 µM) and PI-103 (1 µM), but not by the PI3Kβ isoform inhibitor TGX 221 (100 nM). Pik3cg(-/-)/Pik3cd(-/-)-arteries showed normal vasoconstriction. We conclude that PI3Kα is an important downstream element in vasoconstrictor GPCR signaling, which contributes to arterial vasocontraction via α1-adrenergic receptors. Our results highlight a regulatory role of PI3Kα in the cardiovascular system, which widens the spectrum of gene therapy approaches targeting PI3Kα in cancer cells and tumor angiogenesis and regional blood flow.

Topics: Androstadienes; Animals; Chromones; Class I Phosphatidylinositol 3-Kinases; Class Ib Phosphatidylinositol 3-Kinase; Furans; Mesenteric Arteries; Mice; Mice, Knockout; Morpholines; Neoplasms; Neovascularization, Pathologic; Phenylephrine; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyridines; Pyrimidines; Pyrimidinones; Receptors, Adrenergic, alpha-1; Signal Transduction; Vasoconstriction; Wortmannin

Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.

Topics: Alleles; Allosteric Regulation; Cell Line; Enzyme Stability; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Mutation; Neoplasms; Oncogenes; Phosphorylation; Protein Binding; Protein Conformation; Protein Multimerization; Protein Serine-Threonine Kinases; Pyridones; Pyrimidinones; Quinazolines; raf Kinases; ras Proteins

Although substantial progress has been made regarding the use of molecularly targeted cancer therapies, resistance almost invariably develops and presents a major clinical challenge. The tumor microenvironment can rescue cancer cells from kinase inhibitors by growth-factor-mediated induction of pro-survival pathways. Here we show that epidermal growth factor receptor (EGFR) inhibition by Gefitinib is counteracted by growth factors, notably FGF2, and we assessed the global molecular consequences of this resistance at the proteome and phosphoproteome level in A431 cells. Tandem mass tag peptide labeling and quantitative mass spectrometry allowed the identification and quantification of 22 000 phosphopeptides and 8800 proteins in biological triplicates without missing values. The data show that FGF2 protects the cells from the antiproliferative effect of Gefitinib and largely prevents reprogramming of the proteome and phosphoproteome. Simultaneous EGFR/FGFR or EGFR/GSG2 (Haspin) inhibition overcomes this resistance, and the phosphoproteomic experiments further prioritized the RAS/MEK/ERK as well as the PI3K/mTOR axis for combination treatment. Consequently, the MEK inhibitor Trametinib prevented FGF2-mediated survival of EGFR inhibitor-resistant cells when used in combination with Gefitinib. Surprisingly, the PI3K/mTOR inhibitor Omipalisib reversed resistance mediated by all four growth factors tested, making it an interesting candidate for mitigating the effects of the tumor microenvironment.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Fibroblast Growth Factor 2; Gefitinib; Humans; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Phosphopeptides; Protein Kinase Inhibitors; Proteome; Proteomics; Pyridones; Pyrimidinones; Quinazolines

Targeted therapies elicit seemingly paradoxical and poorly understood effects on tumor immunity. Here, we show that the MEK inhibitor trametinib abrogates cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) from human or mouse myeloid progenitors. MEK inhibition also reduced the production of the mMDSC chemotactic factor osteopontin by tumor cells. Together, these effects reduced mMDSC accumulation in tumor-bearing hosts, limiting the outgrowth of KRas-driven breast tumors, even though trametinib largely failed to directly inhibit tumor cell proliferation. Accordingly, trametinib impeded tumor progression in vivo through a mechanism requiring CD8

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mutation; Myeloid Cells; Myelopoiesis; Neoplasms; Osteopontin; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; T-Lymphocytes

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Sirolimus

Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Area Under Curve; Bridged Bicyclo Compounds, Heterocyclic; Caco-2 Cells; Cell Line, Tumor; Class III Phosphatidylinositol 3-Kinases; Crystallography, X-Ray; Drug Discovery; Enzyme Inhibitors; HeLa Cells; Humans; Male; Mice, SCID; Models, Chemical; Models, Molecular; Molecular Sequence Data; Molecular Structure; Neoplasms; Protein Binding; Protein Structure, Tertiary; Pyrimidinones; Rats, Sprague-Dawley; Sequence Homology, Amino Acid; Thermodynamics; Xenograft Model Antitumor Assays

Attempts to directly block the mutant neuroblastoma rat sarcoma oncogene (NRAS) protein, a driving mutation in many cancer types, have been unsuccessful. Current treatments focus on inhibition of different components of NRAS' two main downstream cascades: PI3K/AKT/mTOR and MAPK. Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines, including melanoma cells, melanoma cells with acquired trametinib resistance, lung cancer and neuroblastoma cells. We show that both of the main downstream cascades of NRAS can be blocked by this combination: metformin indirectly inhibits the PI3K/AKT/mTOR pathway and trametinib directly impedes the MAPK pathway. This dual therapy synergistically reduced cell viability in vitro and xenograft tumor growth in vivo. We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of NRAS mutant cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; GTP Phosphohydrolases; Humans; Immunoblotting; MAP Kinase Signaling System; Membrane Proteins; Metformin; Mice, Nude; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

In this issue of Cancer Cell, Schwartz and colleagues and Costa and colleagues demonstrate that inhibition of PI3Kα or PI3Kβ in cancer cells with hyperactivated PI3Kα or PI3Kβ, respectively, activates the other isoform, leading to a "rebound" of the PI3K activity through different compensation mechanisms.

Topics: Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chromones; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Neoplasms; ortho-Aminobenzoates; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Pyrimidinones; Thiazoles

Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation. Therefore, WEE1 inhibition in H3K36me3-deficient cells results in RRM2 reduction, critical dNTP depletion, S-phase arrest, and apoptosis. Accordingly, this synthetic lethality is suppressed by increasing RRM2 expression or inhibiting RRM2 degradation. Finally, we demonstrate that WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumor xenografts.

Topics: Amino Acid Sequence; Animals; Base Sequence; Blotting, Western; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Histones; Humans; Lysine; Methylation; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Neoplasms; Nuclear Proteins; Nucleotides; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleoside Diphosphate Reductase; RNA Interference; Sequence Homology, Amino Acid; Sequence Homology, Nucleic Acid; Xenograft Model Antitumor Assays

Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kβ in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kβ-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kβ inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110β with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.

Topics: Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Cell Membrane Permeability; Crystallography, X-Ray; Dogs; Drug Screening Assays, Antitumor; Female; Heterografts; Humans; Indoles; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Microsomes, Liver; Molecular Conformation; Molecular Docking Simulation; Neoplasm Transplantation; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Protein Binding; PTEN Phosphohydrolase; Pyrimidinones; Rats; Rats, Nude; Solubility; Stereoisomerism; Structure-Activity Relationship

In clinic, the application of photodynamic therapy (PDT) in deep tissue is severely constrained by the limited penetration depth of visible light needed for activating the photosensitizer (PS). In this Article, a merocyanine 540 (MC540) and upconverting nanoparticle (UCN) coloaded functional polymeric liposome nanocarrier, (MC540 + UCN)/FPL, was designed and constructed successfully for solving this problem in PDT. Compared with the conventional approaches using UCNs absorbing PSs directly, the combination of UCN and polymeric liposome has unique advantages. The UCN core as a transducer can convert deep-penetrating near-infrared light to visible light for activating MC540. The functional polymeric liposome shell decorated with folate as a nanoshield can keep the UCN and MC540 stable, protect them from being attacked, and help them get into cells. The results show that (MC540 + UCN)/FPL is an individual nanosphere with an average size of 26 nm. MC540 can be activated to produce singlet oxygen successfully by upconverting fluorescence emitted from UCNs. After (MC540 + UCN)/FPL was modified with folate, the cell uptake efficiency increased obviously. More interestingly, in the PDT effect test, the (MC540 + UCN)/FPL nanocarrier further improved the inhibition effect on tumor cells by anchoring targeting folate and transactivating transduction peptide. Our data suggest that the (MC540 + UCN)/FPL nanocarrier may be a useful nanoplatform for future PDT treatment in deep-cancer therapy based on upconversion mechanism.

Topics: Cell Line, Tumor; Cells; Humans; Infrared Rays; Liposomes; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polymers; Pyrimidinones

The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF and MAP-ERK kinase (MEK) inhibitor (trametinib) is significantly more active in patients with BRAF-mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of extracellular signal-regulated kinase (ERK). Such adaptive changes in tumor cell signaling networks allow bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR, and many receptor tyrosine kinases such as EGF receptor (EGFR) and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single-agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single-agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses.

Topics: Antineoplastic Combined Chemotherapy Protocols; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Indoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melanoma; Models, Biological; Mutation; Neoplasms; Oximes; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

Inhibition of the monocarboxylate transporter MCT1 by AZD3965 results in an increase in glycolysis in human tumor cell lines and xenografts. This is indicated by changes in the levels of specific glycolytic metabolites and in changes in glycolytic enzyme kinetics. These drug-induced metabolic changes translate into an inhibition of tumor growth in vivo. Thus, we combined AZD3965 with fractionated radiation to treat small cell lung cancer (SCLC) xenografts and showed that the combination provided a significantly greater therapeutic effect than the use of either modality alone. These results strongly support the notion of combining MCT1 inhibition with radiotherapy in the treatment of SCLC and other solid tumors.

Topics: Animals; Biological Transport; Cell Line, Tumor; Cluster Analysis; Disease Models, Animal; Female; Glycolysis; Humans; Lactates; Metabolomics; Monocarboxylic Acid Transporters; Neoplasms; Oxidative Stress; Pyrimidinones; Radiation Tolerance; Symporters; Thiophenes; Tumor Burden; Xenograft Model Antitumor Assays

Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here, we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We show that MK-1775, a potent and selective ATP-competitive inhibitor of WEE1, is cytotoxic across a broad panel of tumor cell lines and induces DNA double-strand breaks. MK-1775-induced DNA damage occurs without added chemotherapy or radiation in S-phase cells and relies on active DNA replication. At tolerated doses, MK-1775 treatment leads to xenograft tumor growth inhibition or regression. To begin addressing potential response markers for MK-1775 monotherapy, we focused on PKMYT1, a kinase functionally related to WEE1. Knockdown of PKMYT1 lowers the EC(50) of MK-1775 by five-fold but has no effect on the cell-based response to other cytotoxic drugs. In addition, knockdown of PKMYT1 increases markers of DNA damage, γH2AX and pCHK1(S345), induced by MK-1775. In a post hoc analysis of 305 cell lines treated with MK-1775, we found that expression of PKMYT1 was below average in 73% of the 33 most sensitive cell lines. Our findings provide rationale for WEE1 inhibition as a potent anticancer therapy independent of a genotoxic partner and suggest that low PKMYT1 expression could serve as an enrichment biomarker for MK-1775 sensitivity.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; DNA Damage; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Humans; Membrane Proteins; Mice; Neoplasms; Nuclear Proteins; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Tumor Burden; Xenograft Model Antitumor Assays

The binding properties of two medicinally important dihydropyrimidinones derivatives 5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (EMPD) and 5-(Ethoxycarbonyl)-6-methyl-4-(4-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (EMCD) with calf-thymus DNA (ctDNA) were investigated by spectroscopy, viscosity, isothermal titration calorimetry (ITC) and molecular modeling techniques. Simultaneously, their biological activities were evaluated with MTT assay method. The binding constants determined with spectroscopic titration and ITC were found to be in the same order of 10(4)M(-1). According to the results of viscosity studies, fluorescence competitive binding experiment and ITC investigations, intercalative binding was evaluated as the dominant binding modes between the two compounds and ctDNA. Furthermore, the results of molecular modeling corroborated those obtained from spectroscopic, viscosimetric and ITC investigations. Evaluation of the antitumor activities of the two derivatives against different tumor cell lines proved that they exhibited significant tumor cell inhibition rate, accordingly blocking DNA transcription and replication. The present results favor the development of potential drugs related with dihydropyrimidinones derivatives in the treatment of some diseases.

Topics: Animals; Antineoplastic Agents; Cattle; Cell Line, Tumor; Cell Proliferation; DNA; Humans; Intercalating Agents; Neoplasms; Pyridones; Pyrimidinones

SIRT1 and SIRT2 are deacetylase enzymes that belong to the sirtuin family and are involved in tumorigenesis. In our screen for small molecules inhibiting SIRT1/2 toxoflavin was identified. Toxoflavin potently inhibited SIRT1 activity in in vitro deacetylase assay using purified SIRT1 protein. SIRT2 activity was also inhibited by toxoflavin less potently than SIRT1 in deacetylase assay in vitro. Toxoflavin exhibited growth inhibition of various cancer cell lines including A549 lung cancer cells with a GI(50) of 48 nM. Toxoflavin treatment in A549 cells increased the acetylated form of p53, which is a substrate of SIRT1. The acetylation levels of α-tubulin, a SIRT2 substrate, were also increased by toxoflavin treatment dose-dependently. Several toxoflavin derivatives were synthesized to determine the preliminary structure-activity relationship of toxoflavin. Some of the toxoflavin derivatives showed highly selective inhibition against SIRT1. In conclusion, this study presented toxoflavin as a potent SIRT1/2 inhibitor with anticancer activity.

Topics: Acetylation; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Humans; Neoplasms; Pyrimidinones; Sirtuin 1; Sirtuin 2; Small Molecule Libraries; Structure-Activity Relationship; Triazines; Tubulin

The cutaneous effects of rapidly accelerated fibrosarcoma kinase B (BRAF) inhibitors are not well understood. Squamous cell carcinoma (SCC), keratoacanthoma, and photosensitivity have been described in patients taking BRAF inhibitors.. To characterize the timing and frequency of skin lesions in patients receiving BRAF inhibitor therapy, we utilized a retrospective case review of 53 patients undergoing treatment with BRAF inhibitors for 4-92 weeks of therapy. Patients were evaluated at baseline, and then followed at 4- to 12-week intervals. Charts were retrospectively reviewed, and the morphology and timing of cutaneous events were recorded.. Thirty-three of the 53 charts met exclusion/inclusion criteria, 15 were treated with vemurafenib, and 18 were treated with GSK 2118436/GSK 1120212. Of 33 patients treated with BRAF inhibitor, 13 developed photosensitivity (39.4%), 10 developed actinic keratoses (30.3%), 10 developed warts (30.3%), and 6 developed SCC (18.2%).. Multiple cutaneous findings were observed in the 33 patients taking BRAF inhibitors. The previously described association with SCC and photosensitivity was observed in these patients as well. Over half of the observed SCCs were invasive in nature. Photosensitivity continues to be frequent with BRAF inhibitors. Patients taking BRAF inhibitors should have regular full body skin exams. Further studies are necessary to better elucidate the rates of these adverse cutaneous effects.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Humans; Imidazoles; Indoles; Keratoacanthoma; Keratosis, Actinic; Male; Melanoma; Middle Aged; Neoplasms; Oximes; Photosensitivity Disorders; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Sulfonamides; Vemurafenib; Warts

Topics: Animals; Astronomical Phenomena; Clinical Trials as Topic; Embryonic Stem Cells; Genes; Global Warming; Humans; Intestines; Mental Disorders; Neoplasms; Patents as Topic; Pyridones; Pyrimidinones; Reference Books; Research Report; Research Support as Topic; Retina; Science

3,4-Dihydropyrimidinones of curcumin were synthesized in excellent yield by multi-component one-pot condensation of curcumin, substituted aromatic aldehydes and urea/thiourea under solvent free conditions using SnCl(2)·2H(2)O catalyst. All the synthesized compounds have been characterized by IR, (1)H NMR, (13)C NMR, Mass spectra as well as elemental analyses. The synthesized compounds 4a-n were evaluated for their synergistic antimicrobial (antibacterial and antifungal) activity against bacteria and fungi. Zone of inhibition was measured by adopting disc diffusion method. In vitro minimum inhibitory concentrations were measured using broth microdilution and food poisoning method. In addition to this in vitro cytotoxicity of synthesized compounds against three human cancer lines Hep-G2, HCT-116 and QG-56 were also evaluated. Most of the compounds showed interesting antimicrobial and cytotoxic activity as compared to curcumin, that is, the compounds derived from 2-hydroxy benzaldehyde, 4-hydroxy benzaldehyde and 4-hydroxy-3-methoxy benzaldehyde showed the highest biological activity as compared to other compounds.

Topics: Anti-Infective Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Drug Design; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Neoplasms; Pyrimidinones

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.

Topics: Animals; Binding Sites; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Computer Simulation; Humans; Mice; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Pyrimidinones; Rats; Structure-Activity Relationship; Transplantation, Heterologous; Up-Regulation

Topics: Antineoplastic Agents; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Uveal Neoplasms

In this study for searching novel B-Raf(V600E) inhibitors, pharmacophore-based virtual screening identified 1 as a hit bearing 5-benzylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-dione. Based on 1, scaffold hopping inspired by molecular docking discovered 5-(furan-2-ylmethylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione as a new and better scaffold. Substructure search with the new scaffold identified 28 active compounds, among which 12 compounds (42.9%) showed IC(50) less than 1 μM. Especially, compound 3o, which is 10-fold more potent than the hit 1, is a potent inhibitor comparable to that of the marketed drug vemurafenib.

Topics: Amino Acid Substitution; Drug Design; Humans; Molecular Docking Simulation; Mutation, Missense; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrimidinones; Structure-Activity Relationship

A small molecule compound, JTP-74057/GSK1120212/trametinib, had been discovered as a very potent antiproliferative agent able to induce the accumulation of CDK inhibitor p15INK4b. To conduct its drug development rationally as an anticancer agent, molecular targets of this compound were identified as MEK1/2 using compound-affinity chromatography. It was shown that JTP-74057 directly bound to MEK1 and MEK2 and allosterically inhibited their kinase activities, and that its inhibitory characteristics were similar to those of the known and different chemotype of MEK inhibitors PD0325901 and U0126. It was further shown that JTP-74057 induced rapid and sustained dephosphorylation of phosphorylated MEK in HT-29 colon and other cancer cell lines, while this decrease in phosphorylated MEK was not observed in PD0325901-treated cancer cells. Physicochemical analyses revealed that JTP-74057 preferentially binds to unphosphorylated MEK (u-MEK) in unique characteristics of both high affinity based on extremely low dissociation rates and ability stabilizing u-MEK with high thermal shift, which were markedly different from PD0325901. These findings indicate that JTP-74057 is a novel MEK inhibitor able to sustain MEK to be an unphosphorylated form resulting in pronounced suppression of the downstream signaling pathways involved in cellular proliferation.

Topics: Allosteric Regulation; Antineoplastic Agents; Benzamides; Butadienes; Chromatography, Affinity; Diphenylamine; Dose-Response Relationship, Drug; HEK293 Cells; HT29 Cells; Humans; Kinetics; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Nitriles; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction

A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment.

Topics: Antineoplastic Agents; Binding Sites; Crystallography, X-Ray; Drug Discovery; Humans; MAP Kinase Kinase Kinases; Models, Molecular; Molecular Structure; Neoplasms; Pyridones; Pyrimidinones

Investigate the efficacy and pharmacodynamic effects of MK-1775, a potent Wee1 inhibitor, in both monotherapy and in combination with gemcitabine (GEM) using a panel of p53-deficient and p53 wild-type human pancreatic cancer xenografts.. Nine individual patient-derived pancreatic cancer xenografts (6 with p53-deficient and 3 with p53 wild-type status) from the PancXenoBank collection at Johns Hopkins were treated with MK-1775, GEM, or GEM followed 24 hour later by MK-1775, for 4 weeks. Tumor growth rate/regressions were calculated on day 28. Target modulation was assessed by Western blotting and immunohistochemistry.. MK-1775 treatment led to the inhibition of Wee1 kinase and reduced inhibitory phosphorylation of its substrate Cdc2. MK-1775, when dosed with GEM, abrogated the checkpoint arrest to promote mitotic entry and facilitated tumor cell death as compared to control and GEM-treated tumors. MK-1775 monotherapy did not induce tumor regressions. However, the combination of GEM with MK-1775 produced robust antitumor activity and remarkably enhanced tumor regression response (4.01-fold) compared to GEM treatment in p53-deficient tumors. Tumor regrowth curves plotted after the drug treatment period suggest that the effect of the combination therapy is longer-lasting than that of GEM. None of the agents produced tumor regressions in p53 wild-type xenografts.. These results indicate that MK-1775 selectively synergizes with GEM to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Cycle Proteins; Cell Line, Tumor; Deoxycytidine; Disease Progression; Drug Synergism; Female; Gemcitabine; Genes, p53; Humans; Mice; Mice, Nude; Mutation; Neoplasms; Nuclear Proteins; Pancreatic Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Tumor Burden; Xenograft Model Antitumor Assays

Radiotherapy is commonly used to treat a variety of solid tumors. However, improvements in the therapeutic ratio for several disease sites are sorely needed, leading us to assess molecularly targeted therapeutics as radiosensitizers. The aim of this study was to assess the wee1 kinase inhibitor, MK-1775, for its ability to radiosensitize human tumor cells.. Human tumor cells derived from lung, breast, and prostate cancers were tested for radiosensitization by MK-1775 using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of MK-1775 to abrogate the radiation-induced G₂ block, thereby allowing cells harboring DNA lesions to prematurely progress into mitosis, was determined using flow cytometry and detection of γ-H2AX foci. The in vivo efficacy of the combination of MK-1775 and radiation was assessed by tumor growth delay experiments using a human lung cancer cell line growing as a xenograft tumor in nude mice.. Clonogenic survival analyses indicated that nanomolar concentrations of MK-1775 radiosensitized p53-defective human lung, breast, and prostate cancer cells but not similar lines with wild-type p53. Consistent with its ability to radiosensitize, MK-1775 abrogated the radiation-induced G₂ block in p53-defective cells but not in p53 wild-type lines. MK-1775 also significantly enhanced the antitumor efficacy of radiation in vivo as shown in tumor growth delay studies, again for p53-defective tumors.. These results indicate that p53-defective human tumor cells are significantly radiosensitized by the potent and selective wee1 kinase inhibitor, MK-1775, in both the in vitro and in vivo settings. Taken together, our findings strongly support the clinical evaluation of MK-1775 in combination with radiation.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Combined Modality Therapy; Female; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Neoplasms; Nuclear Proteins; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Radiation-Sensitizing Agents; Transplantation, Heterologous; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Inhibition of the checkpoint kinase Chk1, both as a monotherapy and in combination with DNA damaging cytotoxics, is a promising therapeutic approach for the treatment of a wide array of human cancers. However, much remains to be elucidated in regard to the patient populations that will respond best to a Chk1 inhibitor and the optimal therapeutics to combine with a Chk1 inhibitor. In an effort to discover sensitizing mutations and novel combination strategies for Chk1 inhibition, an siRNA screen was performed in combination with the selective Chk1 inhibitor AR458323. This screen employed a custom made library of siRNAs targeting 195 genes, most of which are involved in cell-cycle control or DNA damage repair. One of the most prominent and consistent hits across runs of the screen performed in three different cancer cell lines was Wee1 kinase. MK-1775 is a small molecule inhibitor of Wee1 that is currently in early stage clinical trials. In confirmation of the results obtained from the siRNA screen, AR458323 and MK-1775 synergistically inhibited proliferation in multiple cancer cell types. This antiproliferative effect correlated with a synergistic induction of apoptosis. In cellular mechanistic studies, the combination of the two molecules resulted in dramatic decreases in inhibitory phosphorylation of cyclin-dependent kinases, an increase in DNA damage, alterations in cell-cycle profile, and collapse of DNA synthesis. In conclusion, the clinical combination of a Chk1 inhibitor and a Wee1 inhibitor holds promise as an effective treatment strategy for cancer.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; DNA Replication; Drug Synergism; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Neoplasms; Nuclear Proteins; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; RNA, Small Interfering

Cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (N-terminal SH2) domains of p85alpha, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function. They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85alpha. The mutant proteins are still able to bind to the catalytic subunits p110alpha and p110beta. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110alpha, and p110alpha is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85alpha and p110alpha while preserving the stabilizing interaction between p85alpha iSH2 and the adapter-binding domain of p110alpha.

Topics: Adenine; Amino Acid Sequence; Animals; Base Sequence; Blotting, Western; Catalytic Domain; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Chick Embryo; Class I Phosphatidylinositol 3-Kinases; Dioxoles; Fibroblasts; Humans; Immunoprecipitation; Morpholines; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Binding; Protein Subunits; Pyrimidinones; Quinazolines; Thiazolidinediones; Transfection

Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G(2) checkpoint signaling. Because p53 is a key regulator in the G(1) checkpoint, p53-deficient tumors rely only on the G(2) checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G(2) DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; CDC2 Protein Kinase; Cell Cycle Proteins; Cell Line, Tumor; Cyclin B; Cyclin-Dependent Kinases; DNA Damage; Drug Synergism; Flow Cytometry; HeLa Cells; Humans; Neoplasms; Nuclear Proteins; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Rats; Rats, Inbred F344; Rats, Nude; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Eight novel toxoflavin glycosides, which are potential prodrugs in antibody directed enzyme prodrug therapy (ADEPT), were synthesized. The structures of all toxoflavin glycosides were characterized by (13)C NMR spectroscopy, elemental analysis, and MS. Their enzymatic hydrolysis activities were tested against beta-glucosidase (EC.3.2.1.21).

Topics: Antibodies; beta-Galactosidase; Glycosides; Immunotherapy; Magnetic Resonance Spectroscopy; Neoplasms; Prodrugs; Pyrimidinones; Triazines

Topics: Animals; Antineoplastic Agents; Benzamides; Drug Delivery Systems; Drug Design; Drug Screening Assays, Antitumor; Drugs, Investigational; Humans; Kinesins; Neoplasms; Pyrimidinones; Quinazolines; Spindle Apparatus

All the nine 1,3-dialkylated-pyrimidin-2,4-diones investigated are active against all the 59 human tumor cell lines. Compounds 2, 3, 4, and 6 show significant anti-cancer activities at some specific cell lines while compounds 7 and 9 exhibit anti-cancer activities against more number of cell lines. The structure-activity relationship studies indicate that the presence of piperidine/pyrrolidine at the end of C-6 chain, benzoyl group at C-5, and benzyl groups at N-1, N-3 of the pyrimidine ring increases the anti-cancer activities of these molecules.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neoplasms; Piperidines; Propanolamines; Pyrimidines; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship

The inhibitor of apoptosis (IAP) protein survivin is highly expressed in cancers, but not in normal differentiated tissues. TCF/beta-catenin signaling has been reported to participate in the regulation of survivin transcription in colon cancer. We have recently characterized ICG-001, a small molecule specific inhibitor of the beta-catenin/Creb-binding protein (CBP) interaction. Inhibition of the beta-catenin/CBP interaction represses a subset of TCF/beta-catenin-mediated transcription. ICG-001 potently inhibits survivin gene transcription and expression. ICG-001-mediated downregulation of survivin expression enhanced caspase-3 activity and apoptosis, which was rescued by overexpression of wild type but not mutant (C84A) survivin. Small interfering RNA and genetic reduction of CBP also decreased survivin expression. Chromatin immunoprecipitation assay confirmed that CBP is the crucial coactivator for TCF/beta-catenin-mediated survivin transcription. Furthermore, ICG-001-induced recruitment of p300 to the survivin promoter led to concomitant recruitment of SUMO-1, HDAC6 and PML proteins, which have been associated with transcriptional repression. These findings demonstrate that CBP and p300 play very distinct roles in survivin gene transcription.

Topics: Animals; Apoptosis; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Caspases; Cell Line, Tumor; Cytoskeletal Proteins; E1A-Associated p300 Protein; Female; Gene Expression; Humans; Immunoblotting; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Male; Mice; Microtubule-Associated Proteins; Models, Biological; Neoplasm Proteins; Neoplasms; Nuclear Proteins; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction; Survivin; Trans-Activators; Transcription, Genetic

The mechanism of resistance of cancer cells to the anticancer drug cisplatin is not fully understood. Using cisplatin-sensitive KB-3-1 and -resistant KCP-20 cells, we found that the resistant cells have higher membrane potential, as determined by membrane potential sensing oxonol dye. Electron spin resonance and fluorescence polarization studies revealed that the resistant cells have more "fluid" plasma membranes than the sensitive cells. Because of this observed difference in membrane "fluidity," we attempted modification of the plasma membrane fluidity by the incorporation of heptadecanoic acid into KB-3-1 and KCP-20 cell membranes. We found that such treatment resulted in increased heptadecanoic acid content and increased fluidity in the plasma membranes of both cell types, and also resulted in increased cisplatin resistance in the KCP-20 cells. This finding is in accord with our results, which showed that the cisplatin-resistant KCP-20 cells have more fluid membranes than the cisplatin-sensitive KB-3-1 cells. It remains to be determined whether the observed differences in biophysical status and/or fatty acid composition alone, or the secondary effect of these differences on the structure or function of some transmembrane protein(s), is the reason for increased cisplatin resistance.

Topics: Carcinoma; Cell Division; Cell Line, Tumor; Cell Membrane; Cisplatin; Clone Cells; Cyclic N-Oxides; Drug Resistance, Neoplasm; Fatty Acids; HeLa Cells; Humans; Isoxazoles; Membrane Fluidity; Membrane Lipids; Membrane Potentials; Membrane Proteins; Neoplasms; Potassium Channels; Pyrimidinones

The purpose of this study was to determine in a preclinical purging model, how effective crystal violet-mediated photodynamic therapy (CV-PDT) is against solid tumor and drug-resistant mutant tumor cells, and if certain limitations of CV-PDT can be overcome by using crystal violet (CV) in combination with the membrane-active photosensitizer, Merocyanine 540 (MC540). When used under conditions that preserved an adequate fraction of normal human granulocyte/macrophage progenitors (CFU-GM), CV-PDT failed to achieve meaningful reductions of DU145 prostate, H69 small cell lung cancer, and MDA-MB-435S breast cancer cells. Melphalan-resistant L1210/L-PAM1, adriamycin-resistant P388/ADR, and adriamycin-resistant HL-60/ADR leukemia cells were markedly less sensitive to CV-PDT than their wild-type counterparts, whereas cisplatin-resistant H69/CDDP cells were more sensitive than wild-type H69 cells. Sequential exposure to MC540- and CV-PDT under conditions that preserved an adequate fraction (73% and 29%, respectively) of normal CD34-positive hematopoietic stem cells and granulocyte/macrophage progenitors was highly effective against H69 (99.997% reduction) and H69/CDDP (99.999% reduction) cells, but ineffective against HL-60/ADR, MDA-MB-435S, and DU145 cells. CV thus shows only limited promise as a single-modality purging agent. However, in certain situations, clinically meaningful tumor cell depletions can be obtained by using CV in combination with a second photosensitizer such as MC540.

Topics: Animals; Bone Marrow Purging; Caspases; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Gentian Violet; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Mice; Molecular Structure; Necrosis; Neoplasms; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Receptors, Peptide

Topics: Animals; Binding Sites; Bone Marrow Purging; Bone Marrow Transplantation; Hematopoietic Stem Cells; Humans; Neoplasms; Neoplastic Stem Cells; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Transplantation, Autologous

Salicylate and several structurally analogous compounds enhance merocyanine 540 (MC540)-photosensitized killing of leukemia cells (M. A. Anderson, B. Kalyanaraman, and J. B. Feix, Cancer Res., 53: 806-809, 1993). In this work, we show that salicylic acid enhances the binding of MC540 prior to illumination, as well as the light-stimulated uptake of MC540 by target L1210 murine and K562 human leukemia cells. Acetylsalicylic acid, 2,3- and 2,5-dihydroxybenzoic acids, and sodium benzoate also enhance MC540 uptake. The irradiation dose responses for loss of cell survival and enhanced MC540 uptake are well correlated, both being shifted to earlier time points in the presence of salicylate. Salicylic acid also enhanced photodynamic cell killing of A549 lung carcinoma and NIH:OVCAR-3 ovarian carcinoma cells, two cell types which are relatively resistant to MC540-mediated photosensitization. Cellular uptake of the anionic, potential-sensitive oxonol dye, bis-(1,3-dibutylbarbituric acid)-trimethine oxonol, is also increased by salicylate in a dose-dependent fashion. In contrast, cellular uptake of the cationic cyanine dye, 3,3'-dihexyloxacarbocyanine, is unaffected by salicylate. These studies suggest that increased uptake of MC540 is the basis of salicylate enhancement and that changes in plasma membrane potentials may play a mechanistic role in the potentiation of MC540 binding and cell killing.

Topics: Animals; Benzoates; Benzoic Acid; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Fluorescence; Humans; Leukemia; Leukemia L1210; Mice; Neoplasms; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Salicylates; Salicylic Acid

Many new photosensitizers and laser wavelengths are being tested to improve photodynamic therapy by enhancing specific tumor uptake and/or retention, lowering systemic toxicity, and increasing laser tissue penetration. In this study the potential synergistic effects of rhodamine-123 (Rh-123) and merocyanine-540 (MC-540) sensitization of human tumor cell lines after laser exposure were explored. In a first series of experiments, the kinetics of uptake of Rh-123 and M-540 were tested on three human leukemia cell lines (K562, RAJI, 729HF2), P3 squamous carcinoma, and M26 melanoma. Our results demonstrate a clear difference in the rate and amount of uptake of MC-540 (K562 > P3 > RAJI > 729HF2 > M26) and Rh-123 (P3 > RAJI > 729HF2 > K562 > M26) by these cell lines. In a second series of experiments, M26 tumor cells were sensitized with either Rh-123 (1 microgram/ml) or with MC-540 (20 micrograms/ml) alone or with a combination of the two dyes for 60 minutes, then exposed to the argon (514.5 nm) laser at nonthermal energy levels. Our results demonstrate a significant enhancement of the tumoricidal effects of the laser on M26 carcinoma cells after sensitization with both dyes together (MC-540 and Rh-123) when compared to each dye alone. As with combination antibiotherapy, the synergistic effects of two laser dyes that have different intracellular targeting sites appear to enhance tumoricidal effects significantly after exposure to a matching laser wavelength. The data provide evidence for effective laser phototherapy by dye synergy.

Topics: Antimetabolites, Antineoplastic; Burkitt Lymphoma; Carcinoma, Squamous Cell; Cell Survival; Drug Synergism; Fluorescent Dyes; Hot Temperature; Humans; Laser Therapy; Leukemia, B-Cell; Leukemia, Erythroblastic, Acute; Lung Neoplasms; Melanoma; Neoplasms; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Radiation Dosage; Rhodamine 123; Rhodamines; Tumor Cells, Cultured

Merocyanine 540 (MC 540) is a photosensitizing dye that has been used in a phase I clinical trial for the purging of leukemia and lymphoma cells from autologous bone marrow grafts. In this paper we examine the role of plasma membrane negative charge, plasma membrane fluidity, and plasma membrane hydrophobicity in the regulation of a cell's susceptibility to MC 540-sensitized photoirradiation. Among solid tumor cells, we found an inverse correlation between surface electronegativity, affinity for dye molecules, and susceptibility to MC 540-sensitized photoinactivation. That is, the least electronegative cells bound the highest amount of dye and were the most susceptible to dye-sensitized photoirradiation. By contrast, no such correlations were found among leukemia/lymphoma cells. This suggested that dye binding and susceptibility to MC 540-mediated photodynamic damages are regulated differently in hematopoietic/lymphopoietic and solid tumor cells.

Topics: Bone Marrow; Bone Marrow Cells; Cell Membrane; Cell Separation; Humans; Leukemia; Light; Lymphoma; Membrane Fluidity; Neoplasms; Neuraminidase; Pyrimidinones; Radiation-Sensitizing Agents; Solubility; Surface Properties; Trypsin; Tumor Cells, Cultured

MC540-mediated photolysis has several features that make it potentially attractive as a clinical purging procedure. (1) The experience with experimental tumors suggests that MC540-mediated photolysis is effective against a broad range of leukemias and solid tumors, including drug-resistant tumors (Sieber et al., 1984b). Drug-resistant tumor cells are likely to occur in heavily pretreated patients. (2) MC540-mediated photolysis is not cell-cycle dependent (Manna and Sieber, 1985). It kills both resting and cycling cells. In this regard, MC540-mediated photolysis is a valuable complement to cell-cycle specific cytotoxic drugs. (3) There is a large differential in sensitivity between normal pluripotent hematopoietic stem cells and leukemia and neuroblastoma cells. (4) The mechanism of action of MC540-mediated photolysis is different from that of lectins, antibodies and most cytotoxic drugs. MC540 binds to the lipid portion of the plasma membrane and membrane lipids are probably a primary target of the toxic photoproducts. Antibodies and lectins react with proteins and carbohydrates and most drugs have intracellular targets (e.g., nuclear DNA). We would therefore expect little cross-resistance if MC540-mediated photolysis were used in combination with other purging procedures.(5) The small amounts of dye that remain associated with the marrow graft and are infused into the patient are approximately 100,000-fold less than the LD(10) (in mice) and therefore unlikely to cause any harm. The outcome of the first clinical application of the technique supports this view (Sieber et al., 1986c). A better understanding of the underlying molecular mechanisms will undoubtedly lead to more effective applications of the technique and perhaps to the identification of more potent analogs of MC540.

Topics: Bone Marrow; Bone Marrow Transplantation; Humans; Neoplasms; Photolysis; Pyrimidinones; Radiation-Sensitizing Agents; Transplantation, Autologous

Topics: Animals; Bone Marrow Transplantation; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Light; Neoplasms; Pyrimidinones; Transplantation, Autologous

The pharmacokinetics of granulated Damvar (delta-(2-amino-6-hydroxy-3,4-dihydro-4-oxo-5-pyrimidinyl) valeric acid) after a single oral dose of 1000 mg was studied in 10 subjects with neoplastic disease. The rate of Damvar absorption from the digestive tract is not very fast. Maximal serum levels (13.5 micrograms/ml) were recorded 3 h after administration with minor interpersonal variations. The time course of Damvar serum concentrations coincides with its distribution in a two-compartmental pharmacokinetic model with biological half-life of 9.72 +/- 0.84 h. Only a small amount of Damvar is eliminated in urine during a period of 24 h (3.1% of the administered dose). Its renal clearance is also low (0.05 ml/s). The analysis of Damvar excretion in urine shows that kidneys play a minor role in its elimination from the body. Therefore the attention should be concentrated on the effect of Damvar administration in patients with disturbed metabolic functions.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Female; Half-Life; Humans; Kidney; Kinetics; Male; Mathematics; Middle Aged; Neoplasms; Pyrimidinones

Topics: Administration, Oral; Adult; Aged; Antimetabolites; Female; Humans; Male; Middle Aged; Neoplasms; Pyrimidinones

Topics: Animals; Cattle; Cell Line; Cells, Cultured; Clone Cells; Culture Media; Culture Techniques; Diploidy; Fibroblasts; HeLa Cells; Humans; Hypoxanthines; Infant, Newborn; Male; Neoplasms; Phosphotransferases; Polyploidy; Purines; Pyrimidinones; Serum Albumin, Bovine; Triazoles

Topics: Aminohydrolases; Astrocytoma; Central Nervous System; Glioblastoma; Humans; Meningeal Neoplasms; Meningioma; Neoplasms; Phosphates; Pyrimidinones