CHFR Methylation for Predicting Taxane Sensitivity in Lung and Esophageal Cancer

CHFR 甲基化用于预测肺癌和食道癌紫杉烷敏感性

• 批准号: 7892354
• 负责人: JAMES G. HERMAN
• 金额: $ 27.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892354
• 关键词: Adjuvant; Adjuvant Study; Adjuvant Therapy; Alkylating Agents; Biological Assay; Biological Markers; Biology; Biopsy; Blood; Cancer Patient; Cause of Death; Characteristics; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Colon; DNA; DNA Repair; Data; Detection; Diagnostic; Diagnostic tests; Disease; Enrollment; Esophageal; Fluorouracil; Formalin; Freezing; Funding; Gel; Genes; Head and Neck Cancer; Hospitals; Hypermethylation; Individual; Institution; Lung; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Measurable; Methylation; Neoadjuvant Therapy; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; Paclitaxel; Palliative Care; Pathologic; Patients; Performance; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma; Platinum Compounds; Population; Positron-Emission Tomography; Promoter Regions; Prospective Studies; Resected; Retrospective Studies; Ring Finger Domain; Sampling; Sensitivity and Specificity; Source; Specimen; Stomach; Surrogate Markers; Taxane Compound; Testing; Time; Tissues; Tumor Biology; Tumor Burden; Tumor Tissue; United States; Work; advanced disease; base; cancer type; chemotherapeutic agent; chemotherapy; design; docetaxel; irinotecan; prospective; response; taxane; trial comparing; tumor

DESCRIPTION (provided by applicant): Lung and esophageal cancer represent common malignancies which cause the death of >180,000 individuals each year in the United States alone. Currently available chemotherapy both as neoadjuvant treatment and as palliative therapy for advanced disease has had a small but measurable effect on the survival of patients with these diseases. However, while a number of different drugs (for example alkylating agents, platinum compounds, 5FU, and taxanes) are available, no means currently exists for selecting therapy based upon the biology of a patient's individual tumor. We have shown, previously, that DNA hypermethylation associated promoter region silencing of the DNA damage repair gene O6-MGMT, can predict patients sensitive to alkylating agents, and these patients benefit with long-term survival. We now have preliminary data in esophageal cancer patients suggesting that hypermethylation of the checkpoint with forkhead and ring finger domains gene (CHFR) detected by Methylation Specific PCR (MSP) correlates with response to therapy with taxanes and results in prolonged survival of individual patients with CHFR methylation. In the R21 portion of this proposal, we intend to (1) complete a single institution, retrospective trial of neoadjuvant taxane-based therapy in esophageal cancer and extend our analysis to lung cancer patients who also have been treated with neoadjuvant taxanes; (2) detect methylation of CHFR in plasma from patients with esophageal cancer to determine if plasma can be used when tumor tissue is not available; (3) determine the performance characteristics of this assay and compare results between gel-based MSP and real-time MSP for the CHFR gene. In the R33 component of this application, we will validate both our gel-based and real-time tests for CHFR methylation in multi-institutional retrospective studies in lung and esophageal cancer. Then, we intend to apply mainly our real-time assay to prospective studies both in single and multi-institutional settings. These studies, for both neoadjuvant and palliative treatments, will determine the clinical utility of CHFR methylation to predict sensitivity of lung and esophageal cancer to taxanes. They may also provide the basis for targeted use of these agents in other cancer types, including colon, gastric, and head and neck cancer, where CHFR methylation is also frequently observed. Taxanes are a class of chemotherapeutic agents widely used to treat lung and esophageal cancer patients, but many patients do not respond to these drugs. We will further develop a test for CHFR methylation and determine whether CHFR methylation can be used to predict which patients will respond to taxane based chemotherapies.

描述(申请人提供)：肺癌和食道癌是一种常见的恶性肿瘤，仅在美国每年就有18万人死亡。目前，化疗既可作为新的辅助治疗，也可作为晚期疾病的姑息治疗，对这些疾病患者的存活率有很小但可测量的影响。然而，尽管有许多不同的药物(例如烷化剂、铂化合物、5-氟尿嘧啶和紫杉烷)可供选择，但目前还没有根据患者个体肿瘤的生物学来选择治疗方法。我们以前已经证明，DNA损伤修复基因O6-MGMT的DNA高甲基化相关启动子区沉默可以预测对烷基化药物敏感的患者，这些患者受益于长期生存。我们现在有食道癌患者的初步数据表明，甲基化特异性聚合酶链式反应(MSP)检测到带有叉头和环指结构域基因(CHFR)的检查点超甲基化与紫杉烷治疗的反应有关，并导致CHFR甲基化患者的个体生存时间延长。在这项建议的R21部分，我们打算(1)完成一项关于食道癌基于新辅助紫杉烷治疗的单一机构、回顾性试验，并将我们的分析扩展到也接受过新辅助紫杉烷治疗的肺癌患者；(2)检测食道癌患者血浆中CHFR的甲基化状态，以确定在没有肿瘤组织可用的情况下是否可以使用血浆；(3)确定这种检测方法的性能特点，并比较凝胶MSP和实时荧光定量MSP对CHFR基因的检测结果。在该应用程序的R33组件中，我们将在肺癌和食道癌的多机构回顾研究中验证我们的凝胶和实时CHFR甲基化测试。然后，我们打算将我们的实时分析主要应用于单机构和多机构环境下的前瞻性研究。对于新辅助治疗和姑息治疗，这些研究将确定CHFR甲基化预测肺癌和食道癌对紫杉烷类药物敏感性的临床实用性。它们还可能为这些药物在其他癌症类型中的靶向使用提供基础，包括结肠癌、胃癌和头颈癌，在这些癌症中，CHFR甲基化也经常被观察到。紫杉烷是一类广泛用于治疗肺癌和食道癌患者的化疗药物，但许多患者对这些药物没有反应。我们将进一步开发CHFR甲基化测试，并确定CHFR甲基化是否可以用来预测哪些患者对紫杉烷类化疗有反应。