sta-9090 and Skin-Neoplasms

Uveal melanoma (UM) is a rare form of melanoma without effective therapy. The biology of UM relies on several heat-shock protein 90 (Hsp90)-dependent molecules such as MET, MEK and AKT, making Hsp90 inhibition a rational approach. Patients with stage IV UM, measurable disease, and no previous chemotherapy were eligible. Patients received either ganetespib 200 mg weekly (cohort A) or 150 mg twice a week (cohort B). Primary endpoint response rate (RR) was assessed by RECIST. A total of 17 patients were accrued for this study, with seven in cohort A and 10 in cohort B. Liver metastases were present in 59%. Response outcomes included one partial response, four stable disease, 11 progressive disease, and one withdrawal for ORR: 5.9% and disease control rate of 29.4%. Progression-free survival was 1.6 months (cohort A) and 1.8 months (cohort B). Overall survival was 8.5 months (cohort A) and 4.9 months (cohort B). An overall 31% of adverse events were grade 3-4 and were mostly related to gastrointestinal toxicities. Early on-treatment (1 months) positron emission tomography showed reduction in metabolic activity in 24% of patients, suggesting a pharmacodynamic effect of Hsp90 inhibition. These early metabolic changes did not seem to be durable and/or clinically significant in relation to the 2-month response assessment. Hsp90 inhibition with ganetespib resulted in modest clinical benefit on two dosing schedules and was associated with significant, although manageable, gastrointestinal toxicity. Evidence of pharmacodynamic activity for Hsp90 inhibition was observed via positron emission tomography, which did not translate into clinical benefit, suggesting rapid development of resistance.

Topics: Adult; Aged; Aged, 80 and over; Female; HSP90 Heat-Shock Proteins; Humans; Male; Melanoma; Middle Aged; Skin Neoplasms; Triazoles; Uveal Neoplasms

Angiosarcoma is a rare malignant neoplasm derived from endothelial cells, and because advanced angiosarcoma is resistant to standard chemotherapy its prognosis is poor. Therefore, new therapies are urgently needed. Heat shock protein (HSP)90 has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are currently testing the effectiveness of HSP90 inhibitors in various types of malignancies.. To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have antitumour activity.. The expression of HSP90 protein in angiosarcoma was examined using immunohistochemistry and immunoblotting. The effects of HSP90 inhibition were proven using proliferation, migration and invasion assay in angiosarcoma cells. The mechanism of antitumour effect by HSP90 inhibition was investigated by the transfection of small interfering RNA (siRNA).. The levels of HSP90 protein expression in cultured angiosarcoma cell lines were markedly increased compared with those in normal tissue cell lines. Immunohistochemical analyses revealed that the expression of HSP90 protein was strongly detected in angiosarcoma tissues compared with that in normal dermal vessels or senile angioma tissues. Ganetespib, an HSP90 inhibitor, with or without taxanes, inhibited the proliferation of angiosarcoma cells via apoptosis in a dose-dependent manner. HSP90 siRNA suppressed the proliferation, migration and invasion of angiosarcoma cells. Knock-down of HSP90 did not suppress vascular endothelial growth factor receptor 2 directly, but selectively suppressed several downstream targets of vascular endothelial growth factor signalling in angiosarcoma cells.. HSP90 could be a novel therapeutic target for angiosarcoma.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Bridged-Ring Compounds; Case-Control Studies; Cell Movement; Cell Transformation, Neoplastic; Hemangiosarcoma; HSP90 Heat-Shock Proteins; Humans; Signal Transduction; Skin Neoplasms; Taxoids; Triazoles; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Heat shock protein 90 (HSP90) is involved in the regulation of diverse biological processes such as cell signaling, proliferation and survival, and has been recently recognized as a potential target for cancer therapy. Ganetespib is a potent ATP competitive inhibitor of HSP90. Ganetespib downregulated the expression of multiple signal transducing molecules including EGFR, IGF-1R, c-Met, Akt, B-RAF and C-RAF, resulting in pronounced decrease in phosphorylation of Akt and Erk1/2 in a panel of five cutaneous melanoma cell lines including those harboring B-RAF and N-RAS mutations. Ganetespib exhibited potent antiproliferative activity on all five of these cell lines, with IC50 values between 37.5 and 84 nM. Importantly, Ganetespib is active on B-RAF mutated melanoma cells that have acquired resistance to B-RAF inhibition. Ganetespib induced apoptosis and cell cycle arrest at G1 and/or G2/M phase. Ganetespib induced cell cycle arrest was accompanied by altered expression of cyclin-dependent kinase inhibitor (CDKI) p21(Cip1) and p27(Kip1), cyclins B1, D1 and E, and/or cyclin-dependent kinases 1, 2 and 4. HSP90 is functionally important for melanoma cells and HSP90 inhibitors such as ganetespib could potentially be effective therapeutics for melanoma with various genetic mutations and acquired resistance to B-RAF inhibition.

Topics: Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; GTP Phosphohydrolases; HSP90 Heat-Shock Proteins; Humans; Immunoblotting; Inhibitory Concentration 50; Melanoma; Membrane Proteins; Mutation; Phosphorylation; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Skin Neoplasms; Triazoles