Predictive Molecular Markers of Colorectal Cancer For African American Patients

Morehouse School Of Medicine, Atlanta GA

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Abstract

5-Fluorouracil (5FU), the backbone of several chemotherapeutics, is the most commonly used therapeutic agent for colorectal cancer (CRC) treatment (Rx). The anti-tumor activity of 5FU has been related to its ability to induce apoptosis by damaging the DMA and by altering the expression of pro- and anti- apoptotic molecules (e.g. Bax, Bcl-2, p53, etc.). Studies from our laboratory and others, however, have suggested that the prognostic value of abnormal immunohistochemical (IHC) expression of Bax, Bcl-2 and p53 in CRCs will vary with tumor stage, tumor location, and with race/ethnicity of patients who undergo only curative surgery. Nevertheless, such differences in predicting responses to chemotherapy are limited. Moreover, prospective studies to assess the predictive ability of molecules based on patient race/ ethnicity are not available due to the limited enrolment of minority populations into randomized clinical trials. Therefore, well characterized large "retrospective cohort' studies, similar to our proposed studies are needed. Utilizing our well developed methods, in specific aim # 1, we propose to evaluate IHC expression of Bax, Bcl-2 and p53 in tissue sections of primary sporadic Stage II and III CRCs from 1,548 African-Americans (774 of MSM and 774 of UAB), who received 5-FU plus Leucovorin (LV) or 5FU/LV/oxaliplatin adjuvant therapies. The variations in their expression levels will be correlated with time to recurrence and patient survival based on tumor location. In specific aim # 2, we propose to evaluate Stage II and III CRC tissue arrays for IHC expression of a select set of molecular factors from a panel of molecules (TS, TP, DPD, p21waf"1, p27kip"1, Ki67, EGFR, VEGF, and MUC1). These molecular factors based on our preliminary date as well as the literature are likely to be predictors of 5FU/LV and 5FU/LV/oxaliplatin treatment. Their expression levels will be compared between the responders (with a median survival over 3 times longer than nonresponders) and non-responders of 5-FU/LV and 5FU/LV/oxaliplatin Rx. In specific aim 3, DNA from archival tissues will be analyzed for micro-satellite instability (MSI) at 4 CA-dinucleotide MS loci (Mfd27, Mfd41, Mfd47 & Mfd57) and 2 poly-A repeats (BAT25, BAT26). Phenotypic expression of hMLH1, hMSH2, hMSH6 and PMS2 will be used to identify DNA mismatch repair deficient tumors. The phenotypic variations and the status of MS will be correlated with time to recurrence and survival of Stage II & III patients. This aim also proposes to utilize novel data mining techniques to identify complex interactions among multiple factors which influence responses to these 5FU-based therapies. If these approaches identify molecular signatures of 5FU-based therapy efficacy in African-American patients, similar approaches could be potentially extended to other racial groups as well as to other cancer therapeutic agents. These findings will also aid in developing clinical trials for the evaluation of promising molecular signatures of 5FU-based therapy efficacy in colorectal cancer; subsequently, they will help the oncologist in designing individualized therapeutic interventions.