Use of HSP90 inhibitors in the combination immunotherapy of melanoma (P4272)

Abstract

Abstract The molecular chaperone, HSP90 is commonly overexpressed in human melanomas, where it serves to stabilize a broad range of client proteins providing growth, survival and migratory advantages to tumor cells and conditions a pro-angiogenic tumor microenvironment (TME). HSP90-mediated stabilization also limits the proteasome-dependent processing of client proteins and the subsequent presentation of derivative peptides in tumor cell-associated MHC class I complexes which is required for effective host CD8+ T cell recognition of melanoma cells. As a consequence, we have analyzed the anti-tumor impacts of clinical-grade HSP90 inhibitors (i.e. STA9090, 17-DMAG, Novobiocin) on client protein expression in vitro (human melanoma cell line Mel526, murine melanoma cell line B16) and in vivo (s.c. B16 tumors in C57BL/6 mice). We observed that HSP90 inhibitors promote the proteasome-dependent (i.e. blocked by inhibitors PS-341 and MG-132) degradation of client proteins such as c-MET, EphA2, HER2/neu, PDGFRβ and Survivin, with STA9090 appearing to be most efficient on a molar basis. We are currently investigating the capacity of STA9090 to therapeutically sensitize established melanomas to client protein-specific CD8+ T cells (induced by active vaccination or provided via adoptive cell transfer; ACT) in combination therapy approaches. We believe such protocols may hold translational promise for the treatment of patients with advanced-stage melanoma.