Currently 5FU/LV/oxaliplatin (FOLFOX) is the most commonly used therapeutic agent for colorectal cancer (CRC) treatment (Rx). The anti-tumor activity of FOLFOX depends on its ability to induce apoptosis by damaging the DNA 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 (patient survival) 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 (predictive value) are limited. Therefore, in this application, we propose to evaluate a well characterized large """"""""retrospective cohort"""""""" of CRC patients collected from the UAB-Comprehensive Cancer Center (UAB-CCC) who received FOLFOX adjuvant therapy. Utilizing our well developed methods, in specific aim # 1, we propose to evaluate IHC expression of Bax, Bcl-2 and p53 in archival tissue sections of primary sporadic Stage II and III CRCs from 517 non-Hispanic Caucasian patients who received FOLFOX adjuvant therapy between the years 2000-2006 at the UAB hospital. The variations in their expression levels will be correlated with time to recurrence and patient survival based on tumor location.
In specific aim # 2, the phenotypic expression patterns of p53, Bcl-2 and Bax, and a select set of molecular factors from a panel of molecules (TS, TP, DPD, p21waf-1, p27kip-1, Ki67, EGFR, VEGF, and MUC1) will be evaluated in archival tissues, which were evaluated in specific aim 1, using IHC methods. Their expression levels will be compared between the responders (with a median survival over 3 times longer than non-responders) and non-responders of FOLFOX Rx. If these approaches identify molecular signatures of FOLFOX therapy efficacy, similar approaches could be potentially extended 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.
SUMMARY The anti-tumor activity of FOLFOX, currently used therapeutic agent for colorectal cancer (CRC), depends on its ability to induce apoptosis by damaging the DNA and by altering the expression of pro- and anti- apoptotic molecules (e.g. p53, Bcl-2, Bax, etc.). Therefore, this study will evaluate the predictive values of these markers in a well characterized large retrospective cohort of non-Hispanic CRC patients who received FOLFOX adjuvant therapy. The phenotypic variations will be correlated with time to recurrence and survival of these patients. Also proposes to identify multiple factors which influence responses to FOLFOX therapy. These approaches will identify potentially useful predictive markers of FOLFOX therapy efficacy in Stage II and Stage III CRC. The findings will aid in developing clinical trials for the evaluation of these promising molecular markers in prospective clinical trials of CRC;subsequently, they will help the oncologist in designing individualized therapeutic interventions.
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