Abstract 5623: Eliminating pancreatic cancer metastases through inhibition of hedgehog and RAS signaling

Abstract

Abstract Pancreatic cancer is arguably one of the most challenging human malignancies, with the five year survival rate below 5%. Pancreatic cancer is often found in advanced stages, and is unresponsive to conventional cancer therapy. Thus, the need to develop novel treatment strategies targeting metastasis of pancreatic cancer has never been greater. The molecular hallmark of pancreatic cancer is an activating mutation in the small GTPase KRAS. Unfortunately, efforts to target RAS signaling are not very successful for pancreatic cancer treatment. Recently, inhibition of hedgehog (Hh) signaling emerges as a new cancer therapeutic option, but the available data from several current clinical trials in pancreatic cancer show only modest activity. At present, gemcitabine is the standard chemotherapy for metastatic pancreatic cancer but the response rate is less than 10%, with the median survival of only 6-7 months. A new chemotherapy combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) was recently studied in Europe with a response rate of 30% and median survival of 11 months, but at a cost of significant toxicity. In order to design treatment strategies based on the molecular changes critical for cancer metastasis, we took the advantage of the knowledge recently generated in our laboratory and the newly developed molecularly targeted drugs currently in clinical trials. We compared primary pancreatic tumors with metastatic liver tumors for molecular alterations in an orthotopic mouse model, and discovered elevated expression of Indian hedgehog (Ihh) and ERK1/2 phosphorylation in liver metastases. Inhibition of Hh signaling or MEK activity alone reduced primary tumor size but did not significantly affect distal tumor metastases. In contrast, targeting Hh signaling and MEK activity in the orthotopic mouse model dramatically decreased the primary tumor size and nearly eliminated lung and liver metastases. Mice treated with two inhibitors lived two weeks longer than those in other groups. While MEK inhibition mainly interefered with cell proliferation, suppression of ligand-dependent Hh signaling affected the tumor microenvironment. These data indicate that simultaneous suppression of RAS and Hh signaling will be more effective in future pancreatic cancer treatment. 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 5623. doi:1538-7445.AM2012-5623