pyrimidinones and Carcinoma

Uterine serous carcinoma is a distinct histologic subtype of endometrial cancer with an aggressive phenotype, poor prognosis, and limited therapeutic options. A previous proof-of-concept phase II trial of the Wee1 inhibitor adavosertib in uterine serous carcinoma demonstrated evidence of durable clinical activity.. To evaluate the efficacy of adavosertib in women with recurrent or persistent uterine serous carcinoma.. We hypothesize that adavosertib will demonstrate significant clinical activity, as measured by objective response rate, in women with recurrent or persistent uterine serous carcinoma.. Eligible participants will receive adavosertib monotherapy until disease progression or unacceptable toxicity, starting at the recommended phase II dosing of adavosertib 300 mg daily days 1 through 5 and 8 through 12 of a 21-day cycle. Participants will have restaging studies every 6 weeks for the first 48 weeks and then every 9 weeks thereafter.. Patients with histologically confirmed recurrent or persistent uterine serous carcinoma, including endometrial carcinoma of mixed histology where the serous component comprises at least 10% of the tumor, and who have received at least one prior platinum-based chemotherapy regimen for the management of uterine serous carcinoma, are eligible for inclusion in the trial. Participants must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Participants with carcinosarcoma are not eligible.. The primary endpoint is the objective response rate by RECIST 1.1 criteria, as determined by blinded independent central review.. Approximately 120 patients will be enrolled in this trial.. Study completion and presentation of results are projected to be at the end of 2022.. ClinicalTrials.gov: NCT04590248.

Topics: Carcinoma; Cell Cycle Proteins; Clinical Trials, Phase II as Topic; Female; Humans; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones; Uterine Neoplasms

Topics: Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Pyrimidinones; Structure-Activity Relationship

Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and kill tumor cells with naturally inherited or engineered properties. Considering the limitations of OVs monotherapy, combination therapy has been widely explored. MEK inhibitor (MEKi) Trametinib is an FDA-approved kinase inhibitor indicated for the treatment of tumors with BRAF V600E or V600K mutations. In this study, the oncolytic activity in vitro and anti-tumor therapeutic efficacy in vivo when combined with oHSV and MEKi Trametinib were investigated. We found: (1) Treatment with MEKi Trametinib augmented oHSV oncolytic activity in BRAF V600E-mutated tumor cells. (2) Combination treatment with oHSV and MEKi Trametinib enhanced virus replication mediated by down-regulation of STAT1 and PKR expression or phosphorylation in BRAF V600E-mutated tumor cells as well as BRAF wt/KRAS-mutated tumor cells. (3) A remarkably synergistic therapeutic efficacy was shown in vivo for BRAF wt/KRAS-mutated tumor models, when a combination of oHSV including PD-1 blockade and MEK inhibition. Collectively, these data provide some new insights for clinical development of combination therapy with oncolytic virus, MEK inhibition, and checkpoint blockade for BRAF or KRAS-mutated tumors.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Chlorocebus aethiops; Colorectal Neoplasms; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Oncolytic Virotherapy; Oncolytic Viruses; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Simplexvirus; STAT1 Transcription Factor; Vero Cells

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy prevalent in southern China. Presence of treatment-resistant cancer stem cells (CSC) may associate with tumor relapse and metastasis in NPC. ICG-001 is a specific CBP/β-catenin antagonist that can block CBP/β-catenin-mediated transcription of stem cell associated genes and enhance p300/β-catenin-mediated transcription, thereby reducing the CSC-like population via forced differentiation. In this study, we aimed to evaluate the effect of ICG-001 on the CSC-like population, and the combination effect of ICG-001 with cisplatin in the C666-1 EBV-positive NPC cells. Results showed that ICG-001 inhibited C666-1 cell growth and reduced expression of CSC-associated proteins with altered expression of epithelial-mesenchymal transition (EMT) markers. ICG-001 also inhibited C666-1 tumor sphere formation, accompanied with reduced SOX2(hi)/CD44(hi) CSC-like population. ICG-001 was also found to restore the expression of a tumor suppressive microRNA-145 (miR-145). Ectopic expression of miR-145 effectively repressed SOX2 protein expression and inhibited tumor sphere formation. Combination of ICG-001 with cisplatin synergistically suppressed in vitro growth of C666-1 cells and significantly suppressed growth of NPC xenografts. These results suggested that therapeutically targeting of the CBP/β-catenin signaling pathway with ICG-001 can effectively reduce the CSC-like population and combination with cisplatin can effectively suppress the growth of NPC.

Topics: Animals; Antineoplastic Agents; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Synergism; Epithelial-Mesenchymal Transition; Herpesvirus 4, Human; Humans; Hyaluronan Receptors; Mice; Mice, Nude; MicroRNAs; Microscopy, Confocal; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplastic Stem Cells; p300-CBP Transcription Factors; Pyrimidinones; RNA Interference; RNA, Small Interfering; Signal Transduction; SOXB1 Transcription Factors; Transplantation, Heterologous

Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. As radiotherapy is the primary treatment for NPC, this offers a rationale to investigate if uncoupling the DNA damage responses can sensitize this cancer type. The G2 DNA damage checkpoint is controlled by a cascade of protein kinases: ATM/ATR, which phosphorylates CHK1/CHK2, which in turn phosphorylates WEE1. A number of small molecule inhibitors have been developed against these kinases as potential therapeutic agents. Here we demonstrated that compare to that in immortalized nasopharyngeal epithelial cells, ATR, CHK1, and WEE1 were overexpressed in NPC cell lines. Inhibitors of these kinases were unable to promote extensive mitotic catastrophe in ionizing radiation-treated NPC cells, indicating that they are not very effective radiosensitizer for this cancer. In the absence of prior irradiation, however, mitotic catastrophe could be induced with inhibitors against CHK1 (AZD7762) or WEE1 (MK-1775). NPC cells were more sensitive to WEE1 inactivation than nasopharyngeal epithelial cells. Targeting CHK1 and WEE1 together induced more extensive mitotic catastrophe than the individual components alone. Taken together, our results show that NPC cells depend on CHK1 and WEE1 activity for growth and that inhibitors of these kinases may serve as potential therapeutics for NPC.

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Carcinoma; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; DNA Damage; Flow Cytometry; G2 Phase; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mitosis; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Neoplasm Transplantation; Nuclear Proteins; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; RNA Interference; Thiophenes; Urea

Chemoprevention presents a major strategy for the medical management of colorectal cancer. Most drugs used for colorectal cancer therapy induce DNA-alkylation damage, which is primarily repaired by the base excision repair (BER) pathway. Thus, blockade of BER pathway is an attractive option to inhibit the spread of colorectal cancer. Using an in silico approach, we performed a structure-based screen by docking small-molecules onto DNA polymerase β (Pol-β) and identified a potent anti-Pol-β compound, NSC-124854. Our goal was to examine whether NSC-124854 could enhance the therapeutic efficacy of DNA-alkylating agent, Temozolomide (TMZ), by blocking BER. First, we determined the specificity of NSC-124854 for Pol-β by examining in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single nucleotide (SN)- and long-patch (LP)-BER. Second, we investigated the effect of NSC-124854 on the efficacy of TMZ to inhibit the growth of mismatch repair (MMR)-deficient and MMR-proficient colon cancer cell lines using in vitro clonogenic assays. Third, we explored the effect of NSC-124854 on TMZ-induced in vivo tumor growth inhibition of MMR-deficient and MMR-proficient colonic xenografts implanted in female homozygous SCID mice. Our data showed that NSC-124854 has high specificity to Pol-β and blocked Pol-β-directed SN- and LP-BER activities in in vitro reconstituted system. Furthermore, NSC-124854 effectively induced the sensitivity of TMZ to MMR-deficient and MMR-proficient colon cancer cells both in vitro cell culture and in vivo xenograft models. Our findings suggest a potential novel strategy for the development of highly specific structure-based inhibitor for the prevention of colonic tumor progression.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Caco-2 Cells; Carcinoma; Cell Line, Tumor; Colorectal Neoplasms; Dacarbazine; DNA Polymerase beta; Drug Synergism; Female; HCT116 Cells; HT29 Cells; Humans; Mice; Mice, SCID; Molecular Targeted Therapy; Organophosphates; Pyrimidinones; Temozolomide; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Recently, it has been reported that the anti-viral drug, lopinavir, which is currently used as a human immunodeficiency virus (HIV) protease inhibitor, could also inhibit E6-mediated proteasomal degradation of mutant p53 in E6-transfected C33A cells. In this study, C33A parent control cells and HPV16 E6-transfected cells were exposed to lopinavir at concentrations ranging from 0 to 30 microM. The phenotypic response was assessed by Fourier transform infrared (FT-IR) spectroscopy directly on cells (the metabolic fingerprint) and on the cell growth medium (the metabolic footprint). Multivariate analysis of the data using both principal components analysis (PCA) and canonical variates analysis (PC-CVA) showed trends in scores plots that were related to the concentration of the drug. Inspection of the PC-CVA loadings vector revealed that the effect was not due to the drug alone and that several IR spectral regions including proteins, nucleotides and carbohydrates contributed to the separation in PC-CVA space. Finally, partial least squares regression (PLSR) could be used to predict the concentration of the drug accurately from the metabolic fingerprints and footprints, indicating a dose related phenotypic response. This study shows that the combination of metabolic fingerprinting and footprinting with appropriate chemometric analysis is a valuable approach for studying cellular responses to anti-viral drugs.

Topics: Anti-HIV Agents; Carcinoma; Cell Line, Tumor; Female; Humans; Lopinavir; Metabolomics; Oncogene Proteins, Viral; Phenotype; Principal Component Analysis; Pyrimidinones; Repressor Proteins; Spectroscopy, Fourier Transform Infrared; Uterine Cervical Neoplasms

Although HIV protease inhibitor (PI) drugs predominantly target HIV proteases 1 and 2, it is also known that part of their efficacy is due to selective inhibition of the proteasome. The pathogenicity of high-risk human papilloma virus (HPV) is dependent on expression of viral E6 proteins which inappropriately activate the 26S proteasome to degrade p53 and other cellular proteins that are detrimental to viral replication. Comparison of the ability of the PIs indinavir, ritonavir, amprenavir, lopinavir, atazanavir, nelfinavir and saquinavir to inhibit E6-mediated proteasomal degradation of mutant p53 in E6-transfected C33A cells showed that 15 microM lopinavir, 1 mM indinavir or 125 microM ritonavir treatment for 24 h produced a stable increase in the level of nuclear p53 in these cells with minimal cell death. After 4 h exposure of HPV16+ve SiHa cells to 15 microM lopinavir, a transient increase in wild-type p53 expression was observed associated with a 7% reduction in the chymotryptic activity of the 205 proteasome and apoptosis after 24h. Comparison of growth rates of PI treated SiHa, CaSki, C33A, C33A-E6 and non-transformed NIH/3T3 cells showed that SiHa were the most sensitive, whereas NIH/3T3 were least affected. In conclusion, these data show that specific HIV PIs such as lopinavir and possibly indinavir, can induce selective toxicity of HPV-transformed cervical carcinoma cells expressing wild-type p53 and may form the basis of a topically applied alternative to surgery for the treatment of HPV-related premalignant lesions of the cervix.

Topics: Animals; Carcinoma; Cell Line, Tumor; Female; HIV Protease Inhibitors; Humans; Lopinavir; Mice; NIH 3T3 Cells; Oncogene Proteins, Viral; Proteasome Endopeptidase Complex; Pyrimidinones; Repressor Proteins; Transfection; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

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 relationship between tumor cell differentiation and photosensitizer accumulation used in PDT is poorly defined. In the present work, specific cell differentiation of colon carcinoma CT26 cells induced by sodium butyrate was manifested by morphological changes, proliferation and protein expression and was correlated with the accumulation of endogenous and exogenous photosensitizes. Reduced accumulation of the endogenous protoporphyrin IX and the exogenous hypericin and MC540 was detected in differentiated cells. In contrast, a differentiation-dependent increase was measured with TPPS4, TMPyP, the pheophorbides (C5, C6, C12), HypS4 and helianthrone. In conclusion, PpIX, Hypericin and MC540 show specific binding and accumulation in poorly differentiated tumors, giving these tumors tissue-specific advantage in photo-diagnostic PDT applications.

Topics: Animals; Anthracenes; Butyrates; Carcinoma; Cell Cycle; Cell Differentiation; Colonic Neoplasms; Mice; Perylene; Photosensitizing Agents; Protoporphyrins; Pyrimidinones; Tumor Cells, Cultured