Efficacy of the Novel Non-Quinone Based HSP-90 Inhibitor PU-H71 in JAK2V617F and MPLW515L-Induced Murine Models of Myeloproliferative Neoplasms.

Abstract 3898

Poster Board III-834

The discovery of mutations in the JAK-STAT signaling pathway in the majority of patients with myeloproliferative neoplasms (MPN) has led to the development of JAK2 kinase inhibitors for the treatment of these disorders. Although JAK2 inhibitors demonstrate efficacy in preclinical models and in early phase clinical trials, to date, JAK2 inhibitor treatment has not resulted in molecular responses or in improvements in blood counts. We therefore have investigated the effects of additional therapies that might provide benefit to patients with myeloproliferative disorders, including Hsp90 inhibition, which has been shown to abrogate oncogenic signaling pathways in other human malignancies. We analyzed the effect of PU-H71, a novel non-quinone based Hsp-90 inhibitor, in MPN cell lines, primary patient samples, and in animal models. PU-H71 treatment caused potent, dose-dependent inhibition of cell growth in isogenic cell lines expressing JAK2/MPL mutations, JAK2V617F-positive leukemia cell lines, and primary MPN patient samples, which was associated with induction of apoptotic cell death at clinically achievable concentrations. Further, we observed JAK2 degradation in cell lines and primary samples with PU-H71 treatment, and immunoprecipitation experiments documented association of JAK2 with HSP90 and with PU-H71, demonstrating that JAK2 is a client of the HSP90 chaperone complex. PU-H71 potently inhibited downstream signaling pathways, including STAT signaling, MAPK signaling, and AKT signaling in JAK2/MPL positive cell lines and primary samples. Most importantly, in vivo therapy with PU-H71 in mice expressing JAK2V617F or MPLW515L normalized peripheral blood counts, attenuated extramedullary hematopoiesis, and improved survival compared to vehicle treated mice. We observed reduction in total JAK2 expression in target organs from PUH-71 treated mice, and noted in vivo inhibition of signaling pathways in a manner analogous to in vitro studies. Taken together, these data indicate that Hsp90 inhibition, either alone or in combination with JAK2 inhibitors, may prove useful against human MPN.