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）是结肠直肠癌（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和改变促凋亡和抗凋亡分子（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，在crc中，Bax、Bcl-2和p53的免疫组化（IHC）异常表达的预后价值（患者生存）将因肿瘤分期、肿瘤位置和仅接受治疗性手术的患者的种族/民族而异。然而，这种预测化疗反应的差异（预测值）是有限的。因此，在本申请中，我们建议对来自uab -综合癌症中心（UAB-CCC）接受FOLFOX辅助治疗的CRC患者进行特征明确的大型“回顾性队列”评估。利用我们完善的方法，在特定的目的# 1中，我们建议评估517名2000-2006年间在UAB医院接受FOLFOX辅助治疗的非西班牙裔高加索患者原发性散发性II期和III期crc的档案组织切片中Bax， Bcl-2和p53的IHC表达。其表达水平的变化将与复发时间和基于肿瘤位置的患者生存相关。在特定目的# 2中，将使用免疫组化方法评估档案组织中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）中选择的一组分子因子。它们的表达水平将在FOLFOX Rx的应答者（中位生存期比无应答者长3倍以上）和无应答者之间进行比较。如果这些方法确定了FOLFOX治疗效果的分子特征，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，它们将帮助肿瘤学家设计个性化的治疗干预措施。