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/Oxaliptin（FOLFOX）是结直肠癌治疗（CRC）治疗（RX）最常用的治疗剂。 FOLFOX的抗肿瘤活性取决于其通过损害DNA并改变促凋亡分子的表达（例如Bax，Bax，Bcl-2，P53等）来诱导凋亡的能力。但是，我们实验室和其他人的研究表明，CRC中BAX，BCL-2和p53的异常免疫组织化学（IHC）的预后价值（患者存活）将随肿瘤阶段，肿瘤位置以及仅接受治疗手术的患者的种族/族裔而变化。然而，预测对化疗反应（预测价值）的这种差异是有限的。因此，在此应用中，我们建议评估从接受FOLFOX辅助治疗的UAB综合癌症中心（UAB-CCC）收集的CRC患者的大型“回顾性队列”。在特定的目标＃1中，我们提议在特定的目标＃1中评估IHC的表达，Bax，Bcl-2和p53在原发性散发性II和III CRC的档案组织切片中，来自517名非西班牙裔Caucasian患者，这些患者接受了2000-2006年的Folfox辅助治疗。其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的时间相关。在特定的目标＃2中，p53，Bcl-2和Bax的表型表达模式，以及一组分子因子（TS，TP，TP，DPD，P21WAF-1，P21WAF-1，P27KIP-1，KI67，KI67，EGFR，VEGF和MUC1）将在档案中进行评估，这些方法是在档案中评估的，该方法是评估的，该方法是评估的，该方法是评估的，该方法是评估的。它们的表达水平将在响应者（中位生存率比非反应者长3倍）和FOLFOX RX的非反应者之间进行比较。如果这些方法确定了FOLFOX治疗功效的分子特征，则可能将类似的方法扩展到其他癌症治疗剂。这些发现还将有助于开发临床试验，以评估大肠癌中基于5FU的治疗功效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。