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Grant Details

Grant Number: 5R03CA139629-02 Interpret this number
Primary Investigator: Manne, Upender
Organization: University Of Alabama At Birmingham
Project Title: Predictive Molecular Markers of Colorectal Cancer
Fiscal Year: 2010
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Abstract

DESCRIPTION (provided by applicant): 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.

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Publications

Prognostic significance and gene expression profiles of p53 mutations in microsatellite-stable stage III colorectal adenocarcinomas.
Authors: Katkoori VR, Shanmugam C, Jia X, Vitta SP, Sthanam M, Callens T, Messiaen L, Chen D, Zhang B, Bumpers HL, Samuel T, Manne U
Source: PLoS One, 2012;7(1), p. e30020.
EPub date: 2012 Jan 19.
PMID: 22276141
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miRNAs are stable in colorectal cancer archival tissue blocks.
Authors: Bovell L, Shanmugam C, Katkoori VR, Zhang B, Vogtmann E, Grizzle WE, Manne U
Source: Front Biosci (Elite Ed), 2012 Jan 1;4, p. 1937-40.
EPub date: 2012 Jan 1.
PMID: 22202009
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Development and progression of colorectal neoplasia.
Authors: Manne U, Shanmugam C, Katkoori VR, Bumpers HL, Grizzle WE
Source: Cancer Biomark, 2010;9(1-6), p. 235-65.
PMID: 22112479
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Evaluation of lymph node numbers for adequate staging of Stage II and III colon cancer.
Authors: Shanmugam C, Hines RB, Jhala NC, Katkoori VR, Zhang B, Posey JA Jr, Bumpers HL, Grizzle WE, Eltoum IE, Siegal GP, Manne U
Source: J Hematol Oncol, 2011 May 28;4, p. 25.
EPub date: 2011 May 28.
PMID: 21619690
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miRNAs as biomarkers for management of patients with colorectal cancer.
Authors: Manne U, Shanmugam C, Bovell L, Katkoori VR, Bumpers HL
Source: Biomark Med, 2010 Oct;4(5), p. 761-70.
PMID: 20945991
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Prognostic value of mucin 4 expression in colorectal adenocarcinomas.
Authors: Shanmugam C, Jhala NC, Katkoori VR, Wan W, Meleth S, Grizzle WE, Manne U
Source: Cancer, 2010 Aug 1;116(15), p. 3577-86.
PMID: 20564074
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Comparison of the predictive qualities of three prognostic models of colorectal cancer.
Authors: Anderson B, Hardin JM, Alexander DD, Grizzle WE, Meleth S, Manne U
Source: Front Biosci (Elite Ed), 2010 Jun 1;2, p. 849-56.
EPub date: 2010 Jun 1.
PMID: 20515758
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Quantitative Estimation of IL-6 in Serum/Plasma Samples Using a Rapid and Cost-Effective Fiber-Optic dip-probe.
Authors: Wang CW, Manne U, Reddy VB, Kapoor R
Source: Proc Soc Photo Opt Instrum Eng, 2010 Jan 23;7559(75590G), p. null.
PMID: 21785531
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