thiourea and Small-Cell-Lung-Carcinoma

Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose (MTD) levels of amuvatinib with standard chemotherapy regimens and to define the safety profiles of specific amuvatinib + standard regimens.. Five therapies each co-administered with amuvatinib 100-800 mg/day every 21 days were evaluated in treatment-naïve or moderately pre-treated subjects: paclitaxel IV followed by carboplatin IV; carboplatin IV followed by etoposide; topotecan IV; docetaxel IV; and erlotinib by mouth.. Among 97 treated subjects, no treatment arm reached the MTD. Dose-limiting toxicities included febrile neutropenia and diarrhea. No pharmacokinetic interactions of amuvatinib with any cancer regimens occurred. Of 12/97 (12 %) partial responses overall, 11 were seen in the amuvatinib and paclitaxel/carboplatin or carboplatin/etoposide arms and most commonly in the neuroendocrine (NE), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) tumors. Forty-four subjects (45 %) had stable disease. Adverse events reflected combination treatment and were primarily non-hematologic (fatigue, alopecia, diarrhea, nausea, anorexia) and hematologic (neutropenia, anemia, thrombocytopenia, leukopenia). Pharmacodynamic effects as measured by decreased levels of RAD51 and increased residual DNA damage (53BP1 foci) were seen in skin punch biopsies.. Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cohort Studies; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Female; Half-Life; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Small Cell Lung Carcinoma; Thiourea; Tumor Burden

Topics: Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Carboplatin; Clinical Decision-Making; Disease Progression; Etoposide; Humans; Immunoconjugates; Irinotecan; Liver Neoplasms; Lung Neoplasms; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Nivolumab; Paclitaxel; Piperazines; Pyrimidines; Salvage Therapy; Small Cell Lung Carcinoma; Temozolomide; Thiourea; Topotecan

The cellular N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (c-MET) protein is the receptor tyrosine kinase for hepatocyte growth factor. We recently found that c-MET protein expression and activation were enhanced in the majority of small cell lung cancer cell lines with cytotoxic anticancer drug resistance, and that down-regulation of c-MET reduced resistance to these drugs.. Expression of c-MET was studied in three non-small cell lung cancer (NSCLC) cell lines, including six resistant cell strains to cytotoxic anticancer drugs. To assess the effect of c-MET activation on drug resistance, we studied drug sensitivity in the presence of a novel c-MET inhibitor TAS-115.. c-MET expression and activation are also enhanced in some cytotoxic anticancer drug-resistant NSCLC cell lines, and inhibition of c-MET activation by TAS-115 reduced resistance of these cell lines to anticancer drugs.. The mechanism of cellular resistance to anticancer drugs via hepatocyte growth factor/c-MET signal activation is not restricted to small cell lung cancer cell lines, and TAS-115 might be able to reverse the drug resistance of these cancer cells.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Quinolines; Small Cell Lung Carcinoma; Thiourea