DESCRIPTION (provided by applicant): Cancers of the colon and rectum (colorectal cancer) remain a major cause of morbidity and mortality. Since metastatic colorectal cancer remains largely incurable for patients with surgically non-resectable disease, the development of models of metastatic colorectal cancer remains a priority. The availability of a mouse tumor model that demonstrates invasion and/or metastasis and has prominent similarity to human colorectal cancer would provide a powerful tool for identifying the genetic and molecular alterations that lead to malignancy as well as for assessment of therapeutic and preventive strategies. We have recently developed a novel model of invasive colorectal cancer in Smad3+/-;Rab25-/- mice, which develop invasive colon cancers by 8-10 months of age that are identifiable by non-invasive PET and MRI imaging and express high levels of Src and Src activity. The Smad3+/-;Rab25-/- mouse therefore represents a unique model for colorectal cancer in humans and may be of considerable value as a pre-clinical tool for evaluating therapeutic efficacy. We have hypothesized that the Smad3+/-;Rab25-/- mouse provides a robust mouse model of colon cancer with high correlation to human disease. The present proposal seeks to develop this model in two specific aims: First, we will evaluate the differences in RNA expression patterns in Smad3+/-;Rab25-/- mouse colorectal tumors that could account for increased invasive characteristics. RNA sequencing results in tumors will be compared with both other mouse models and human colorectal cancers to determine the correlative characteristics of this model. Common biomarkers will be validated by immunochemistry and quantitative PCR to obtain a greater understanding of the invasive cancer phenotype. Second, we will utilize PET and MRI imaging of colorectal tumors in the Smad3+/-;Rab25- /- mouse to evaluate therapeutic strategies in colorectal cancer. We will assess the efficacy of AZD-0530, a Src kinase family inhibitor, in modulating the progression of invasive colorectal cancers in the Smad3+/-;Rab25-/- mouse model using both imaging and pathological criteria. These studies will facilitate the development of the Smad3+/- ;Rab25-/- mouse model of colon cancer as a critical venue for the evaluation of pre- clinical therapeutic interventions in invasive colorectal cancer.

PUBLIC HEALTH RELEVANCE: Colon cancer is a major cause of cancer death in the USA. A major problem for preclinical research on colon cancer is the lack of useful invasive colon cancer models in mice. This proposal seeks to develop a novel model of invasive colon cancer in mice that recapitulates many of the critical aspects of human colon cancer.