imetelstat and vatalanib

Functional blood vasculature is essential for tumor progression. The main signalization pathways that play a key role in the survival and growth of tumor vessels originate from the VEGF-, PDGF- and FGF tyrosine kinase receptors. In the past decade, significant results have been published on receptor tyrosine kinase inhibitors (RTKIs). In this paper, the mechanisms of action and the results so far available of experimental and clinical studies on multi-target antiangiogenic TKIs are discussed. On the one hand, notable achievements have been made recently and these drugs are already used in clinical practice in some patient populations. On the other hand, the optimal combination and dosage of these drugs, selection of the apropriate biomarker and better understanding of the conflicting role of PDGFR and FGFR signaling in angiogenesis remain future challenges.

Topics: Angiogenesis Inhibitors; Animals; Axitinib; Benzenesulfonates; Humans; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Sunitinib

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.

Topics: Antineoplastic Agents; Benzamides; Benzenesulfonates; Disease Progression; Drug Resistance, Neoplasm; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Mutation; Neoplasm Proteins; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperazines; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Pyrimidines; Pyrroles; Receptor, Platelet-Derived Growth Factor alpha; Sorafenib; Staurosporine; Sunitinib; Thiazoles

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States. Therapeutic agents that target the underlying biology of this disease are necessary to improve outcomes. Angiogenesis plays a central role in NSCLC tumor growth and metastases. The vascular endothelial growth factor pathway (VEGF) as a therapeutic target was recently validated in NSCLC. Since then, a multitude of early phase clinical trials that incorporate the use of angiogenesis inhibitors, either as single agents or in combination with cytotoxic chemotherapy, have been conducted in advanced, refractory NSCLC. This article reviews these clinical trials with attention to toxicity, efficacy, and direction of further study. The data from these trials suggest that optimal use of anti-angiogenic agents in NSCLC is more likely in combination with standard cytotoxic agents, however the most effective combination with the least toxicity is yet to be determined.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Indoles; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib; Treatment Outcome

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, and it is characterized by the occurrence, in > 90 % of cases, of a gain of function mutation in the c-kit proto-oncogene. STI-571 (imatinib mesylate), a selective KIT tyrosine kinase inhibitor, has changed the natural history of this disease, since it has shown high effectiveness in metastatic GIST, and it is currently under investigation also in the adjuvant and neoadjuvant setting. Mechanisms of resistance to imatinib mesylate include both de novo, and, more frequently, acquired resistance, which may occur after several months of drug administration and possibly depends, in most cases, upon an acquired second mutation. In order to overcome imatinib mesylate resistance, the addition of other drugs may be considered in patients who have less than an optimal response to imatinib mesylate monotherapy. Investigational agents that are being studied in this setting include the mammalian target of rapamycin (mTOR) inhibitor RAD 001 and the protein kinase C inhibitor PKC412. In addition, other KIT tyrosine kinase inhibitors with anti-VEGF receptor inhibitory activity, such as SU11248, PTK787/ZK787 and AMG 706, are currently being explored as second line monotherapy for imatinib mesylate-resistant GIST. Finally, another new drug, ecteinascidin (ET-743), that blocks cell cycle progression in G2/M phase through a p53-independent apoptotic mechanism, has shown important preclinical and clinical activity against a number of human solid tumors, including GIST.

Topics: Antineoplastic Agents; Benzamides; Chemotherapy, Adjuvant; Dioxoles; Drug Resistance, Neoplasm; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Neoadjuvant Therapy; Niacinamide; Oligonucleotides; Phthalazines; Piperazines; Proto-Oncogene Mas; Pyridines; Pyrimidines; Pyrroles; Sunitinib; Tetrahydroisoquinolines; Trabectedin

Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.

Topics: Adenosine Triphosphate; Caco-2 Cells; Combinatorial Chemistry Techniques; Drug Design; Humans; Indoles; Molecular Structure; Niacinamide; Oligonucleotides; Phthalazines; Pyridines; Structure-Activity Relationship; Thiazoles; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2