Abstract 2726: Tumor progression and treatment response characterization in a novel mouse model of colon cancer.
Authors: Hadac Jamie N. , Paul Olson Terrah J. , Newton Michael A. , Kennedy Gregory D. , Schelman William R. , Halberg Richard B. 
Published: August 2014

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the U.S. Currently, patients with resected stage II and III disease are considered for adjuvant chemotherapy on a 5-fluorouracil (5FU)-based regimen. Despite receiving post-operative therapy, almost 50% of patients with stage III cancer recur. While 5FU-based chemotherapy has been in clinical use for many decades, there is no accurate predictor of chemotherapeutic response. Prior studies examining this question have been unsuccessful in establishing a clinically relevant predictive molecular signature due to various limitations, including in vitro analysis of cancer cell lines which do not fully recapitulate disease complexity and analysis of hetereogeneously treated human samples of various tumor types. The purpose of this study was to identify molecular differences in colon tumors that are resistant or sensitive to 5FU treatment using the laboratory mouse. Specifically, we aimed to (1) develop and characterize a new mouse model of colon cancer and (2) identify tumors differences in gene expression between tumors that are resistant or sensitive to 5FU.

Methods: Long-lived (SWRxB6)F1.ApcMin/+ (F1.Min) mice were treated with the inflammatory agent dextran sodium sulfate to promote tumors in the distal colon. Colonoscopy was used to identify and longitudinally follow and biopsy individual tumors. To better define chemotherapy response, only tumors that exhibited no detectable size changes over 4 weeks were biopsied and treated with 5FU. Mice were treated with 5FU and serial biopsies were collected.

Results: Tumors in the F1.min mouse exhibit multiple size changes including growth, stasis, and spontaneous regression. Notably, a majority of tumors become static in size after an initial period of growth. Histological evaluation of all tumors revealed that whereas many tumors remained adenomas (71%), some advanced to intramucosal carcinomas (23%) and adenocarcinomas (3%). 2/7 tumors remained static in size as measured by the ratio of tumor-to-lumen cross sectional area, indicative of resistance to 5FU. 3/7 tumors regressed (33.8%-66.0% reduction) which is indicative of sensitivity. Response characteristics could not be assessed in 2/7 tumors due to limited sensitivity in this imaging and measurement system.

Conclusions: F1.Min mice develop tumors that can progress to invasive adenocarcinomas and tumor response to treatment with chemotherapy agents can be followed in real time. More tumors will be treated and in the future will be analyzed for gene expression differences via RNA microarray to identify a molecular signature that may predict 5FU response/resistance. Defining expression patterns that predict outcomes to chemotherapy in CRC could minimize the risk of undergoing ineffective chemotherapy as well as identify patients that may benefit from other treatment approaches in the adjuvant setting.

Citation Format: Jamie N. Hadac, Terrah J. Paul Olson, Michael A. Newton, Gregory D. Kennedy, William R. Schelman, Richard B. Halberg. Tumor progression and treatment response characterization in a novel mouse model of colon cancer. [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 2726. doi:10.1158/1538-7445.AM2013-2726