Evaluation of Oral EGFR Inhibitors in Colorectal Cancer

描述（由申请人提供）：尽管最近在治疗方面取得了进展，但结直肠癌是美国癌症死亡率的第三大原因，晚期疾病的生存率仍然极低。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，并在经验证的定量药效学试验中开发特定的专业知识，以帮助细胞信号传导抑制剂的临床开发。虽然使用EGFR抑制剂和化疗的联合试验在其他癌症类型中是阴性的，但EGFR是结直肠癌的有效靶点，并且吉非替尼与FOLFOX联合的II期试验显示出令人印象深刻的80%的缓解率。在其他肿瘤类型（如肺癌）中观察到的EGFR突变在结直肠癌中未见。这类药物在这种疾病中显然是活跃的，但最佳患者选择，对结直肠肿瘤的确切影响以及反应的预测因素都是重要的未知数。 该应用程序是围绕两个IRB批准的协议。具体目标#1是一项在晚期疾病背景下联合口服EGFR TKI厄洛替尼与FOLFOX/贝伐珠单抗的I期研究。候选人是该试验的主要研究者，并开发和协调生物学研究，其中包括对患者子集治疗前和治疗后活检中EGFR信号传导的定量分析。具体目标#2是一项II期试验，完全由候选人（共同主要研究者）撰写，将吉非替尼添加到基于新辅助5-FU的放化疗中治疗可切除的直肠癌。所有受试者将接受治疗前和治疗后肿瘤和正常结肠活检，以评价药物的生物学效应。在这两项研究中，活检发生在EGFR抑制剂单药治疗的“导入”期后，以分析其在没有其他治疗的情况下的作用。这两项试验的中心主题是将EGFR抑制剂合理地纳入结直肠癌的治疗，以及增加我们对EGFR抑制剂药理作用的理解。

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.