Abstract 3737: The PI3K/mTOR inhibitor PWT33597 regresses 786-0 renal xenografts

Abstract

Abstract PWT33597 is a balanced dual inhibitor of phosphatidylinositol 3-kinase alpha (PI3K alpha) and mTOR, currently in clinical development. Inhibition of signaling downstream of PI3K and mTOR by PWT33597 has been demonstrated, and PWT33597 is strongly efficacious in multiple xenograft models tested to date with different PIK3CA and PTEN genotypes. Inhibitors of mTORC1 (rapalogs) are approved for treatment of advanced renal cell carcinoma (RCC), but their effect is restricted to a subset of patients, and is not sustained. Inhibitors of VEGFR signaling such as sorafenib and sunitinib have also demonstrated clinical activity in RCC and are approved in this indication. Based on the proven role of rapalogs in RCC, we tested PWT33597 in a renal xenograft model with the hypothesis that inhibition of both mTORC1 and mTORC2, as well as PI3K, may offer increased efficacy by direct targeting of multiple signaling nodes including VEGFR signaling. Dual inhibition would also be expected to decrease release of negative feedback loops triggered by either mTOR or PI3K inhibition alone. PWT33597 was tested in 786-0 (VHL -/-, PTEN -/-) xenografts in comparison to rapamycin (mTORC1 inhibitor), and sorafenib (VEGFR/RAF inhibitor). While sorafenib and rapamycin showed tumor growth inhibition (TGI), the maximal effect with sorafenib was 64% TGI, and rapamycin had a largely cytostatic effect. The overall efficacy observed with PWT33597 was superior, with 93% TGI observed. PWT33597 was also tested in comparison to a pan-PI3K inhibitor (GDC-0941, 49% TGI) and demonstrated superior efficacy. Immunohistochemical analysis of tumors for cleaved caspase 3 (CC3) as an indicator of apoptosis showed that a single dose of PWT33597 induced a several fold increase in CC3 staining, and this effect was also apparent after 18 days of dosing. Based on these results we tested the ability of PWT33597 to regress large 786-0 tumors (approx. 500 mm3), and a rapid decrease in tumor size was observed in 100% of animals. Additional cellular and xenograft studies in RCC models are ongoing to further define the mechanism of action of PWT33597, and will be presented. Taken together, these data provide rationale for testing PWT33597 in patients with RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3737. doi:1538-7445.AM2012-3737