Evaluation of Oral EGFR Inhibitors in Colorectal Cancer

描述(申请人提供)：尽管最近在治疗方面取得了进展，但结直肠癌仍是美国癌症死亡的第三大原因，晚期疾病的存活率仍然非常低。该项目的长期目标是研究口服表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)在结直肠癌中的临床活性和生物学效应，并开发一种有效的、定量的药效学分析方法，以帮助临床开发细胞信号抑制物。虽然使用EGFR抑制剂和化疗的联合试验在其他类型的癌症中都是阴性的，但EGFR是结直肠癌的有效靶点，联合使用吉非替尼和FOLFOX的II期试验显示了令人印象深刻的80%的有效率。在其他类型的肿瘤中发现的EGFR突变，如肺癌，在结直肠癌中尚未发现。这类药物显然在这种疾病中是活跃的，但最佳的患者选择、对结直肠肿瘤的确切影响以及应答的预测因素都是重要的未知因素。 该应用程序围绕两个IRB批准的协议构建。具体目标#1是一项在晚期疾病环境下将口服EGFR TKI erlotinib与FOLFOX/贝伐单抗相结合的I期研究。候选人是这项试验的主要研究员，并开发和协调了生物学研究，其中包括对部分患者治疗前和治疗后活组织检查中的EGFR信号进行定量分析。具体目的#2是一项完全由候选人(联合首席研究员)编写的II期试验，在可切除直肠癌的新辅助5-FU基础上加用吉非替尼。所有受试者都将在治疗前和治疗后进行肿瘤和正常结肠活检，以评估药物的生物效果。在这两项研究中，活组织检查发生在使用EGFR抑制剂的单一治疗的导入期之后，以分析它们的影响，而不进行其他治疗。这两个试验的中心主题都是将EGFR抑制剂合理地应用于结直肠癌的治疗，以及增加我们对EGFR抑制剂药理作用的了解。

DESCRIPTION (provided by applicant): Despite recent advances in treatment, colorectal cancer is the third leading cause of cancer mortality in the US, and survival for advanced disease remains extremely low. The long-term objectives of this project are to investigate the clinical activity and biologic effects of oral Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKI) in colorectal cancer, and to develop a specific expertise in validated, quantitative pharmacodynamic assays to aid in the clinical development of cell signaling inhibitors. Although combination trials using EGFR inhibitors and chemotherapy were negative in other cancer types, EGFR is validated target in colorectal cancer, and a phase II trial combining gefitinib with FOLFOX has shown an impressive 80% response rate. EGFR mutations seen in other tumor types such as lung cancer have not been seen in colorectal cancer. This class of agents is clearly active in this disease, but optimal patient selection, the exact effects on colorectal tumors, and predictors of response are all significant unknowns. This application is structured around two IRB-approved protocols. Specific Aim #1 is a phase I study combining the oral EGFR TKI erlotinib with FOLFOX/bevacizumab in the advanced disease setting. The candidate is the principal investigator of the trial, and developed and coordinated biologic studies which include quantitative analysis of EGFR signaling in pre- and post-treatment biopsies in a subset of patients. Specific Aim #2 is a phase II trial written entirely by candidate (co-Principal Investigator) adding gefitinib to neoadjuvant 5-FU based chemoradiation for resectable rectal cancer. All subjects will have pre- and post-treatment tumor and normal colon biopsies to evaluate the biologic effects of the drugs. In both studies, biopsies occur after a "lead-in" period of monotherapy with the EGFR inhibitors to dissect their effects without other treatment. The central theme of both trials is to rationally incorporate EGFR inhibitors into the treatment of colorectal cancer as well as to increase our understanding of EGFR inhibitor pharmacological actions.