Abstract 2356: Characterization of molecular signatures predicting response to 5-FU based chemotherapy in mouse models of colorectal cancer
Authors: Hadac Jamie N. , Olson Terrah J. Paul , Leystra Alyssa A. , Albrecht Dawn M. , Clipson Linda , Sullivan Ruth , Newton Michael A. , Halberg Richard B. , Schelman William R. 
Published: May 2015

Background: Colorectal cancer (CRC) often arises from adenomatous polyps that progress to invasive cancer, but polyps can also remain static in size, regress, or resolve. Predicting which progress and which remain benign is difficult, since longitudinal analysis of individual polyps is impossible due to removal in humans. There are currently no molecular signatures that can identify adenomas that will eventually progress. In patients with stage II and III CRC , adjuvant chemotherapy on a 5-fluorouracil (5FU)-based regimen is considered following surgery. Despite receiving post-operative therapy, almost 50% of patients with stage III cancer recur. Again, there is no molecular signature that can predict response to 5FU. The purpose of this study was to identify gene expression differences in colon tumors using a mouse model. Individual tumors in mice can be monitored longitudinally throughout progression and treatment. Specifically, we aimed to: (1) develop and characterize a new mouse model of colon cancer; (2) identify differences in molecular progression prior to histopathologcial progression; and (3) identify a priori differences in gene expression between tumors that are resistant or sensitive to 5FU.

Methods: (SWRxB6)F1.ApcMin/+ (F1.Min) mice were treated with the inflammatory agent dextran sodium sulfate to induce tumors in the distal colon. Colonoscopy was used to identify, follow, and biopsy individual tumors. To best define chemotherapy response, only tumors that exhibited stasis for 4 weeks prior were treated with 5FU. Gene expression was analyzed from serial biopsies from pre- and post-treatment tumor using microarray and qPCR.

Results: Tumors in F1.Min mice exhibit growth, stasis, and spontaneous regression. A majority of tumors become static in size after an initial period of growth. Histological evaluation of tumors revealed that many tumors remained adenomas (71%), while some advanced to intramucosal carcinomas (23%) and adenocarcinomas (3%). Interestingly, 3 tumors that remained adenomas and 3 that progressed to intramucosal carcinomas displayed differential expression of 68 genes regardless of time point. Analysis of pre-5FU biopsies from 5 resistant tumors and 6 sensitive tumors revealed differential expression patterns of Hp1bp3 and Xpo7.

Conclusions: F1.Min mice develop tumors that can progress to invasive adenocarcinomas, and tumor response to treatment with chemotherapy can be followed in real time. Differential expression of genes with prognostic benefit can occur early and can be sustained throughout tumor development. Molecular determinants of 5FU sensitivity can be identified prior to treatment. Defining expression patterns that predict outcomes to chemotherapy in CRC might minimize the risk of undergoing ineffective chemotherapy and identify patients that may benefit from other treatment approaches in the adjuvant setting.

Citation Format: Jamie N. Hadac, Terrah J. Paul Olson, Alyssa A. Leystra, Dawn M. Albrecht, Linda Clipson, Ruth Sullivan, Michael A. Newton, Richard B. Halberg, William R. Schelman. Characterization of molecular signatures predicting response to 5-FU based chemotherapy in mouse models of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2356. doi:10.1158/1538-7445.AM2014-2356