Development of Mechanism-Based Anticancer Therapy

描述（由申请人提供）：这个职业发展奖的目的是获得支持，设计和进行临床试验，利用新的，基于机制的代理，同时也指导研究员和初级教师在早期临床试验研究的纪律。 临床和转化研究的总体目标是开发针对特定生物学改变的治疗结直肠癌的新方案，从而产生不仅更有效，而且比当前化疗方案毒性更低的策略。研究提案的具体目标是：1）开发基于机制的治疗结直肠癌的临床前模型，其使用双重VEGF-R和EGF-R酪氨酸激酶抑制剂ZD 6474、化疗和塞来昔布靶向肿瘤和内皮细胞，2）开发新的靶向药物组合（无化疗），影响信号转导和促生存因子，作为最佳缓解后CRC的潜在维持方案，和3）在转移性CRC患者中临床测试特定目标1和2中开发的方案，结合详细的药理学、生物学和成像研究，以评估药物暴露、生物学效应和患者益处之间的关系。这些具体目标反映了主要研究者的兴趣和专业知识领域，并展示了本提案资助的假设驱动研究的重点。为了促进医生在高质量的以患者为导向的研究的培训，主要研究者将继续在发展治疗学的培训和指导计划，将利用上述具体目标和重点课程作为一种手段，以推进研究员和初级教师的职业生涯在疾病导向的临床和转化癌症研究。

DESCRIPTION (provided by applicant): The purpose of this career development award is to obtain support to design and conduct clinical trials that utilize novel, mechanism-based agents while also mentoring fellows and junior faculty in the discipline of early clinical trials research. The overall objective of the clinical and translational research is to develop novel regimens for the treatment of colorectal cancer that target specific biological alterations thereby resulting in strategies that are not only more effective, but also potentially less toxic than current chemotherapy regimens. The Specific Aims of the research proposal are to: 1) Develop preclinical models of mechanism-based therapy for colorectal cancer that targets both tumor and endothelial cells using the dual VEGF-R and EGF-R tyrosine kinase inhibitor, ZD6474, chemotherapy, and celecoxib, 2) Develop novel combinations of targeted agents (without chemotherapy) that impact upon signal transduction and pro-survival factors as potential maintenance regimens in CRC after best response, and 3) Clinically test the regimens developed in Specific Aims 1 and 2 in patients with metastatic CRC, incorporating detailed pharmacological, biological and imaging studies to assess the relationships between drug exposure, biological effect and patient benefit. These Specific Aims reflect the areas of interest and expertise of the Principal Investigator and demonstrate the focus of hypothesis-driven research that would be funded by this proposal. To facilitate the training of physicians in high quality patient-oriented research, the Principal Investigator will continue a training and mentoring program in Developmental Therapeutics which will utilize the above Specific Aims and a focused curriculum as a means to advance the careers of fellows and junior faculty in disease-directed clinical and translational cancer research.