Person:

Marmarelis, Melina Elpi

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) p21Cip1 and p27Kip1, 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.

Blockade of the immunological checkpoint programmed death 1 (PD-1) using monoclonal antibodies has shown robust anti-tumor activity across a broad range of solid and hematological malignancies including melanoma and renal cell carcinoma (RCC). Characteristic markers such as the presence of tumor infiltrating lymphocytes, PD-L1 status, and mutational load may be equally or even more important in predicting clinical benefit from PD-1 pathway blockade than tumor histology. This case of a patient with concurrent metastatic melanoma and metastatic RCC, both of which were controlled for more than a year after a single dose of the anti-PD-1 antibody pembrolizumab, illustrates the potential to simultaneously treat distinct immunogenic tumors with anti-PD-1 agents.