Abstract #1922: Antitumor activity of CUDC-305, a novel oral HSP90 inhibitor, in solid and hematological tumor xenograft models

Targeting HSP90 pharmacologically appears to offer a unique anticancer strategy of considerable promise. HSP90 inhibitors suppress multiple client oncoproteins involved in cancer cell proliferation, survival, invasion and angiogenesis to achieve abrogation of cancer phenotypes. CUDC-305 is a potent HSP90 inhibitor of a novel class of synthetic small molecules and has been selected for clinical development. CUDC-305 exhibits favorable pharmacological properties, including high oral availability, high exposure and prolonged retention in tumors, as well as durable biological effects in in vitro and in vivo experiments. Efficacy studies in preclinical tumor xenograft models using various human cancer cell lines support potent anticancer activity of CUDC-305 against a broad range of cancer types. CUDC-305 displays potent antitumor activity in NSCLC orthotopic and subcutaneous xenograft models of H1975, a cell line resistant to EGFR inhibitors as a result of a secondary mutation (T790M). This result suggests antitumor activity of CUDC-305 is independent of EGFR mutation status. CUDC-305 has also demonstrated efficacy in animal models of NSCLC using cell lines carrying other gene mutations or amplifications (such as K-Ras) that result in resistance to EGFR inhibitors (erlotinib, gefitinib). Pharmacodynamic (PD) studies demonstrate CUDC-305 potently down-regulates client proteins involved in cell cycle progression/survival pathways with concurrent induction of HSP70 and apoptosis. In addition to its potent activity against solid tumors, CUDC-305 exhibits remarkable efficacy in hematological tumors. Treatment of CUDC-305 induces complete tumor regression in subcutaneous MV4-11 AML xenografts of various pretreatment tumor sizes (100 mm³ - 900 mm³). PD studies in the same tumor model demonstrate dramatic reduction of oncoprotein FLT3 and downstream signaling molecules with concurrent induction of HSP70 following CUDC-305 treatment. In summary, CUDC-305 is a novel, synthetic oral small molecule inhibitor of HSP90 with potent, durable biological effects in solid as well as hematological tumors. Its potent antitumor effect is presumably attributed to its selective retention in tumor, and its ability to block multiple signaling pathways simultaneously, resulting in effective interruption of interactive networks of signaling pathways in cancer cells. Therefore, CUDC-305 was nominated a drug candidate for further development.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1922.