Rectal Cancer: Molecular Markers of Outcome and Toxicity

直肠癌：结果和毒性的分子标志物

• 批准号: 6874536
• 负责人: HEINZ JOSEF LENZ
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-29 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874536
• 关键词: DNA repair; RNA; angiogenesis; clinical research; cytotoxicity; drug resistance; fluorouracil; gene expression; genetic markers; genetic polymorphism; human subject; laser capture microdissection; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; outcomes research; polymerase chain reaction; rectum neoplasms; vitamin metabolism

DESCRIPTION (provided by applicant): The goal of this study is to identify molecular markers (gene expression levels and germline polymorphisms) associated with clinical outcome and toxicity among Dukes' stage B2, B3 or C rectal cancer patients treated with fluorouracil (5-FU) based chemotherapy and radiation. Failure of adjuvant therapy represents a major problem in rectal cancer, and acute gastrointestinal and hematologic toxic effects are considerable and can be life-threatening. Establishing associations between molecular markers of drug resistance, treatment response, and clinical toxicity, may ultimately result in more successful and less toxic chemotherapeutic regimens for rectal cancer patients. As part of initial studies, we have shown that intratumoral gene expression (e.g., dipyrimidine dehydrogenase) and germline polymorphisms (e.g., thymidylate synthase, TS) can predict response and overall survival in patients with metastatic colon cancer treated with 5-FU. We propose to focus on markers in several key pathways, including 5-FU and folate metabolism, DNA repair, and angiogenesis. Among 788 patients with rectal cancer registered to a collaborative Phase III study of rectal cancer (INT-0144, SWOG 9304) we will determine 1) whether intratumoral gene expression levels (RNA) of enzymes involved in folate and 5-FU metabolism, DNA repair, and growth factors, are associated with clinical outcome; and 2) whether germline polymorphisms (DNA) of genes encoding proteins involved in 5-FU and folate metabolism, detoxification and DNA repair, or angiogenesis, are associated with toxicity and clinical outcome. The study uses a large clinical trial patient population with excellent assessment of outcomes and toxicities, and utilizes existing specimens for a cost-effective approach. Results from this study may aid in the development of future treatment strategies for patients with rectal cancer.

描述（由申请人提供）：这项研究的目的是鉴定与公爵B2期，B3或C型直肠癌患者在氟尿嘧啶（5-FU）基于基于氟尿嘧啶（5-FU）的临床结果和毒性相关的分子标志物（基因表达水平和种系多态性）。辅助治疗的失败是直肠癌的主要问题，急性胃肠道和血液学毒性作用是相当大的，可能会威胁生命。建立耐药性，治疗反应和临床毒性的分子标志物之间的关联，最终可能导致直肠癌患者更成功，毒性更少的化学治疗方案。作为初步研究的一部分，我们已经表明，肿瘤内基因表达（例如二酰胺脱氢酶）和种系多态性（例如，胸腺替基合酶，TS）可以预测接受5-FU治疗的转移性结肠癌患者的反应和整体存活。我们建议将重点放在几种关键途径中的标记上，包括5-FU和叶酸代谢，DNA修复和血管生成。在直肠癌协作研究（INT-0144，SWOG 9304）的788例直肠癌患者中，我们将确定1）1）涉及叶酸和5-FU代谢，DNA修复和生长因子的酶内基因表达水平（RNA）是否与临床结构相关； 2）编码涉及5-FU和叶酸代谢，解毒和DNA修复或血管生成的蛋白质的生殖线多态性（DNA）是否与毒性和临床结果有关。该研究使用了大型临床试验患者人群，对结局和毒性进行了很好的评估，并利用现有标本进行具有成本效益的方法。这项研究的结果可能有助于为直肠癌患者制定未来的治疗策略。