Predictive Molecular Markers of Colorectal Cancer

结直肠癌的预测分子标志物

• 批准号: 7901545
• 负责人: UPENDER MANNE
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901545
• 关键词: Adjuvant Therapy; Adverse effects; African American; American; Anatomy; Anxiety; Apoptosis; Apoptotic; Cancer Patient; Caring; Caucasians; Caucasoid Race; Cessation of life; Clinical; Clinical Trials; Colorectal Adenocarcinoma; Colorectal Cancer; Confounding Factors (Epidemiology); Curative Surgery; DNA Damage; Data; Diagnosis; Diagnostic Neoplasm Staging; Disease; Epidermal Growth Factor Receptor; Ethnic Origin; Evaluation; Fluorouracil; Genes; Grant; Hispanics; Hospitals; Laboratories; Lead; Location; Malignant Neoplasms; Methods; Molecular; Molecular Profiling; Mucin-1 Staining Method; Not Hispanic or Latino; Nuclear; Oncologist; Operative Surgical Procedures; Pathologic; Patients; Pattern; Predictive Factor; Predictive Value; Progression-Free Survivals; Proteins; Race; Randomized Clinical Trials; Recommendation; Recurrence; Relapse; Research Personnel; Resistance; Role; Staging; Statistical Methods; TP53 gene; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Treatment Efficacy; Tumor stage; University of Alabama at Birmingham Cancer Center; Variant; Vascular Endothelial Growth Factors; base; cancer therapy; chemotherapy; cohort; cost; design; experience; high risk; molecular marker; oxaliplatin; palliative; prognostic; prospective; response; tumor

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.

描述（由申请人提供）：目前5FU/LV/奥沙利铂（FOLFOX）是结直肠癌（CRC）治疗（Rx）最常用的治疗剂。 FOLFOX 的抗肿瘤活性取决于其通过破坏 DNA 以及改变促凋亡分子和抗凋亡分子（例如 Bax、Bcl-2、p53 等）的表达来诱导细胞凋亡的能力。然而，我们实验室和其他实验室的研究表明，结直肠癌中 Bax、Bcl-2 和 p53 的免疫组织化学 (IHC) 异常表达的预后价值（患者生存率）将随肿瘤分期、肿瘤位置以及种族/民族的不同而变化。只接受根治性手术的患者。然而，这种预测化疗反应（预测价值）的差异是有限的。因此，在本申请中，我们建议评估从 UAB 综合癌症中心 (UAB-CCC) 收集的接受 FOLFOX 辅助治疗的 CRC 患者的特征明确的大型“回顾性队列”。利用我们成熟的方法，在具体目标#1中，我们建议评估 517 名接受 FOLFOX 辅助治疗的非西班牙裔白种人患者的原发性散发性 II 期和 III 期 CRC 档案组织切片中 Bax、Bcl-2 和 p53 的 IHC 表达2000 年至 2006 年期间在 UAB 医院工作。它们的表达水平的变化将与基于肿瘤位置的复发时间和患者存活率相关。在具体目标#2中，p53、Bcl-2和Bax的表型表达模式，以及从一组分子（TS、TP、DPD、p21waf-1、p27kip-1、Ki67、EGFR、 VEGF 和 MUC1) 将在档案组织中进行评估，这些组织是使用 IHC 方法在特定目标 1 中进行评估的。将比较 FOLFOX Rx 的应答者（中位生存期比无应答者长 3 倍以上）和无应答者之间的表达水平。如果这些方法确定了 FOLFOX 治疗功效的分子特征，那么类似的方法可能会扩展到其他癌症治疗药物。这些发现还将有助于开展临床试验，以评估基于 5FU 的结直肠癌治疗效果的有希望的分子特征；随后，他们将帮助肿瘤学家设计个性化的治疗干预措施。