Abstract 2737: Spontaneous genomic alterations identified in a chimeric model of colorectal cancer guide effective combinatorial therapy.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Colon cancer is the second most common cause of cancer mortality in the western world. We generated a mouse model of colon cancer in which a conditional mutation of p53 is combined with inducible delta131-beta-Catenin over-expression in the intestinal epithelium. After 4-12 months of beta-Catenin induction, small adenomas and large solitary nodules of invasive adenocarcinomas developed in either the upper or lower intestinal tract, while the remainder of the intestine appeared normal. Molecular analysis revealed that EGFR and MET were expressed in advanced adenocarcinomas but not early stage adenomas. Although propagating mouse colon tumors has been very challenging, we nevertheless successfully established one tumor line through direct in vivo propagation in the kidney capsule. This tumor line, CB42, grew aggressively and metastasized to ancillary lymph nodes as well as the lung in a subcutaneous metastasis assay and grew in the liver when seeded there by intra splenic injection. Treatment with a MET inhibitor Crizotinib, had no effect on either primary tumor growth, or metastasis. By comparing the genome of CB42 with other colon tumors that did not propagate, we discovered an amplicon on chromosome five containing genes that correlated with propagation and metastasis. In addition, whole genome sequencing revealed that CB42 harbored a mutation in KRAS. Results from combination therapies against key genetic alterations will be presented. Citation Format: Yinghui Zhou, William M. Rideout, Angela Bressel, Sireesha Yalavarthi, Tong Zi, Anthony Monti, Steve Bottega, Bin Feng, M. Isabel Chiu, Marcus Bosenberg, Joerg Heyer. Spontaneous genomic alterations identified in a chimeric model of colorectal cancer guide effective combinatorial therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2737. doi:10.1158/1538-7445.AM2013-2737