Predictive Molecular Markers of Colorectal Cancer

描述（由申请方提供）：目前，5 FU/LV/奥沙利铂（FOLFOX）是结直肠癌（CRC）治疗（Rx）最常用的治疗药物。FOLFOX的抗肿瘤活性取决于其通过损伤DNA和通过改变促凋亡和抗凋亡分子（例如Bax、Bcl-2、p53等）的表达诱导凋亡的能力。然而，我们实验室和其他研究表明，CRC中Bax、Bcl-2和p53的异常免疫组化（IHC）表达的预后价值（患者生存率）将随肿瘤分期、肿瘤位置和仅接受根治性手术的患者的种族/民族而变化。然而，这种差异在预测化疗反应（预测值）是有限的。因此，在本申请中，我们建议评估一个充分表征的大型“回顾性队列”的CRC患者，这些患者是从UAB综合癌症中心（UAB-CCC）收集的，接受FOLFOX辅助治疗。利用我们成熟的方法，在特定目标#1中，我们建议评价2000-2006年间在UAB医院接受FOLFOX辅助治疗的517例非西班牙裔白人患者的原发性散发性II期和III期CRC存档组织切片中Bax、Bcl-2和p53的IHC表达。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率相关。在特定目标2中，将使用IHC方法在特定目标1中评价的存档组织中评价p53、Bcl-2和Bax的表型表达模式以及来自一组分子（TS、TP、DPD、p21 waf-1、p27 kip-1、Ki 67、EGFR、VEGF和MUC 1）的一组选定分子因子。将在FOLFOX Rx的应答者（中位生存期是非应答者的3倍以上）和非应答者之间比较其表达水平。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，以评估结直肠癌中基于5 FU的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。

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.