Predictive Molecular Markers of Colorectal Cancer

描述(申请人提供)：目前，5FU/LV/Oxaliplatin(FOLFOX)是最常用的结直肠癌(CRC)治疗药物(Rx)。FOLFOX的抗肿瘤活性依赖于其通过损伤DNA和改变促凋亡和抗凋亡分子(如Bax、Bcl2、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，Bax、Bcl2和P53免疫组织化学(IHC)异常表达在癌组织中的预后价值(患者生存期)将因肿瘤分期、肿瘤位置和仅接受根治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，在这项应用中，我们建议评估从UAB-综合癌症中心(UAB-CCC)收集的接受FOLFOX辅助治疗的大量结直肠癌患者的特点。利用我们成熟的方法，在特定的目标#1中，我们建议评估在2000-2006年间在UAB医院接受FOLFOX辅助治疗的517名非西班牙裔高加索患者的散发性原发II期和III期癌的档案组织切片中Bax、Bcl2和P53的IHC表达。它们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期相关。在特定目标2中，将使用IHC方法在特定目标1中评估档案组织中P53、Bcl2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)中选择一组分子因子。它们的表达水平将在FOLFOX Rx的应答者和非应答者之间进行比较(中位生存期比无应答者长3倍以上)。如果这些方法确定了FOLFOX治疗疗效的分子特征，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发临床试验，以评估基于5FU的结直肠癌治疗疗效的有希望的分子标记；随后，它们将帮助肿瘤学家设计个性化的治疗干预措施。

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.