Abstract LB-374: The Hh inhibitor IPI-926 enhances tumor perfusion and nab-paclitaxel activity in a pancreatic xenograft model

Abstract

Abstract Malignant activation of the Hedgehog (Hh) pathway is associated with multiple tumor types. In certain cancers, such as pancreatic, a paracrine role for the Hh ligand has been described, wherein cancer cells produce Hh ligand that activates the Hh pathway in the surrounding stroma. Consistent with this model, IPI-926, a potent and selective Smoothened (Smo) inhibitor, blocks Hh signaling in the mouse stroma -but not in the cancer cells- of several pancreatic xenograft models. We recently published (Olive, Science 2009) that IPI-926 increases vascular perfusion and enhances gemcitabine drug delivery to tumors in a genetically engineered mouse model of pancreatic cancer (KPC) leading to an increase in overall survival. To determine if similar effects could be observed in xenograft models of human pancreatic cancer, experiments were designed to study the combination of IPI-926 with nab-paclitaxel, an agent that has recently demonstrated anti-tumor activity in pancreatic cancer (Van Hoff, ASCO 2009). While IPI-926 had no single agent activity in the L3.6pl human pancreatic xenograft model, it enhanced the activity of nab-paclitaxel from 61% tumor growth inhibition (nab-paclitaxel alone) to 83% tumor growth inhibition (nab-paclitaxel plus IPI-926, p=0.0048). Tumor IHC analysis of phosphohistone 3 showed a higher frequency of cells arrested at the late G2/M phase in the IPI-926 plus nab-paclitaxel group versus nab-paclitaxel alone (p=0.02). One possible explanation for the synergistic effect of a combination of IPI-926 and nab-paclitaxel is that IPI-926 affects the mouse stroma and increases tumor perfusion and nab-paclitaxel accessibility to the tumor. Tumor perfusion was directly measured in IPI-926 treated and untreated animals using contrast enhanced ultrasound. In tumor bearing animals treated with IPI-926 for 7 days, the ultrasound data showed greater tumor perfusion with IPI-926. On average, the peak time for contrast agent levels decreased from 11.0 seconds to 4.75 seconds in the vehicle versus IPI-926 treated animals, respectively, (p=0.0321). These data suggest that the mechanism of synergy between IPI-926 and nab-paclitaxel is likely enhanced drug delivery to the tumor through the effect of IPI-926 on the stroma. Studies are ongoing to measure nab-paclitaxel and paclitaxel levels in IPI-926 treated and untreated tumors, and to investigate these findings with the KPC in situ mouse model of pancreatic cancer. These preclinical data provide a strong rationale for evaluating the Hh inhibitor IPI-926 not only with the current standard of care, gemcitabine, but with emerging new potential therapies like nab-paclitaxel in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-374.