Abstract B145: The novel Hedgehog pathway inhibitor IPI-926 delays metastatic spread and provides a survival benefit in an experimental model of pancreatic liver metastasis.

Abstract

Abstract Metastasis, or the spread of disseminated tumor cells to and colonization of distal sites, is a major cause of cancer mortality. The Hedgehog (Hh) signaling pathway is normally involved in embryogenesis; however recent evidence suggests a role for this pathway in cancer and metastasis. Thus, inhibitors of Hh signaling may have potential utility as novel targeted anti-tumor therapies. IPI-926 is a novel, selective, small molecule that antagonizes the Hh pathway by binding to the Smoothened receptor, the major upstream facilitator of Hh signal transduction, and is currently in phase 2 clinical trials for pancreatic cancer, chondrosarcoma and primary myelofibrosis. Administration of IPI-926 in combination with gemcitabine inhibits incidence of metastases in a KRAS/p53 transgenic model of pancreatic cancer (Olive et al., 2009), supporting an integral role for the Hh pathway in this process. To further explore the activity of IPI-926 in the setting of metastasis, we developed an experimental model of pancreatic cancer liver metastasis where luciferase-tagged tumor cells were implanted in the liver via an intra-splenic injection, followed by splenectomy, resulting in liver metastases. Tumor burden, as assessed by bioluminescence and survival were employed to evaluate IPI-926 activity utilizing different dosing regimens. While treatment of tumor-bearing animals with established disease provided no survival benefit, IPI-926 administered on the day of cell implant provided modest but reproducible increase in survival. However, prophylactic administration of IPI-926 beginning 14 days (d) prior to cell implant resulted in a significant decrease in disease burden and enhanced survival. The activity was dependent on the schedule of IPI-926 administration. Treatment initiated 14d prior to cell implant was more effective than 7d before cell implant, and treatment started only 2d prior to cell implantation showed no difference compared to treatment initiated on the day of cell implant. Histological analysis of pre-treated vs control livers confirmed decreased metastatic nodule formation. In addition, analysis of serum harvested from IPI-926 14d pre-treated vs control animals showed down-regulation of components of the VEGF, PDGF and MMP pathways, suggesting that IPI-926 modulation of these pathways may be involved in the observed effects on metastatic spread. The activity of IPI-926 was also evaluated in the setting of sunitinib enhancement of metastases (Ebos et al., 2010) in the above model. As has been shown previously, short, high-dose sunitinib administration resulted in striking increases in disease burden and shortening of survival compared to control animals. However, when IPI-926 was administered 14d prior to cell implant and sunitinib treatment, disease burden and survival were returned to the levels observed in the control group. In summary, IPI-926 administration delays metastasis in an experimental model of pancreatic liver metastasis and in response to high-dose anti-angiogenic therapy. These results provide rationale for the evaluation of IPI-926 as adjuvant/neoadjuvant therapy to help control metastatic spread post surgical resection in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B145.