Abstract A234: In vivo RNAi screening to identify major players in pancreatic tumor maintenance and growth.

Abstract

Abstract Pancreatic cancer is one of the leading causes of cancer-related death in the United States and no effective therapeutic options are currently available. The lethality of pancreatic cancer, due to the aggressiveness of the disease and the lack of effective treatment, underscores the urgency for a clinical solution. Nevertheless the multiple failures suffered in clinical trials involving diverse compounds and approaches point to the necessity of a better understanding of the disease, in particular of the molecular and cellular mechanisms underlying tumor development and progression. We aim to identify new therapeutic targets for pancreatic cancer treatment by performing in vivo RNAi screens, either in combination with Gemcitabine treatment to isolate modulators of drug response or without any treatment seeking for genes that play a fundamental role in tumor growth and maintenance. Our model system is a cancer cell line derived from a genetically engineered mouse model that develops spontaneous pancreatic ductal adenocarcinoma (PDAC) after activation of a kras mutant (G12D) allele concomitantly with the deletion of the tumor suppressor p53 specifically in the pancreas. This cell line can be effectively transplanted orthotopically in syngeneic mice and preliminary data suggest that we can represent about 3.000 hairpins out of 10.000 per tumor when injecting 30.000 cells orthotopically in the pancreas in the absence of chemotherapy. Genes with established function in pancreatic cancer like Claudin4 and PDGFR scored as hits in the screening, and about 8 more were selected for further validation. In addition, our data show that the transplanted tumors are partially resistant to Gemcitabine treatment in vivo, despite the in vitro sensitivity, which indicate that the system is suitable for a synthetic lethal screen. We have established a model system suitable for in vivo screening in pancreatic cancer, either with or without chemotherapy. We challenged the complexity of pancreatic cancer by functional screening in order to focus our attention on potential key player of tumor progression with plausible clinical relevance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A234. Citation Format: Silvia Fenoglio, Yadira Soto-Feliciano, Gregory Hannon, Michael Hemann. In vivo RNAi screening to identify major players in pancreatic tumor maintenance and growth. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A234.