The Anti-Tumor Activity Of The Smoothened Inhibitor Ipi-926 In Models Of Residual Disease Is Time Dependent

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Although response rates can be high for some solid tumors and hematologic malignancies following treatment, cure rates are low and there is a need to extend the duration of response and overall survival after remission. This relapse is attributed to the presence of residual malignant cells that remain undetected after primary treatment and in many instances the presence of these residual tumor cells eventually leads to disease recurrence and shortened survival. The role of the Hedgehog (Hh) pathway in cancer has been well established, with both ligand-independent signaling due to genetic mutations, as well as ligand-dependent signaling, in which Hh signaling occurs either directly to the tumor cells or to the tumor microenvironment being observed. Moreover, it has been shown that Hh ligand produced by tumor cells acts on stromal cells and inhibition of this interaction results in alterations to the tumor-associated stroma and significant inhibition of tumor growth. IPI-926 is a potent and selective Hh pathway antagonist that inhibits the key signaling membrane protein Smoothened (Smo). IPI-926 delays tumor regrowth post-cytoreduction with either standard of care chemotherapy or targeted therapy in pre-clinical xenograft models of small cell lung (SCLC), non-small cell lung (NSCLC) and prostate cancer. Data reported here show that the activity of IPI-926 in this post-therapy setting exhibits a strict time-dependence, or “efficacy window”. In both the Lx-22 SCLC and H1650 NSCLC models, delaying the time between cytoreductive therapy and initiation of IPI-926 treatment resulted in significant loss of anti-tumor activity. To investigate the molecular consequences underlying this loss of activity, RT-PCR analysis of tumors from different time points post therapy was performed. These results showed upregulation of human Hh ligand in the tumors in response to cytoreductive therapy with subsequent increased Hh signaling in the murine-derived stromal cells. IPI-926 abrogated this signaling. In addition, histological and immunohistochemical analysis demonstrated that IPI-926 induced significant changes in the tumor microenvironment post therapy. Taken together, these data suggest that the administration of IPI-926 post cytoreductive therapy could potentially be beneficial in the residual disease setting in multiple cancer types and warrants further investigation. Moreover, the timing of IPI-926 administration post therapy is critical for this benefit. IPI-926 is currently being evaluated in three Phase 2 clinical trials designed to explore multiple approaches to target ligand-dependent activation of the Hh pathway: 1) a randomized Phase 2 trial in combination with gemcitabine in patients with metastatic pancreatic cancer; 2) a randomized Phase 2 in patients with metastatic or locally advanced chondrosarcoma; and 3) a single-arm Phase 2 trial in patients with myelofibrosis. 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 979. doi:1538-7445.AM2012-979