Development of Mechanism-Based Anticancer Therapy

描述（由申请人提供）：该职业发展奖的目的是获得支持，以设计和实施使用新颖的、基于机制的药物的临床试验，同时指导早期临床试验研究学科的研究员和初级教员。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结直肠癌治疗新方案，从而产生比目前的化疗方案不仅更有效，而且潜在毒性更小的策略。研究计划的具体目的是：1)利用VEGF-R和EGF-R酪氨酸激酶抑制剂ZD6474、化疗和塞来昔布，建立针对肿瘤和内皮细胞的基于机制的结直肠癌治疗的临床前模型；2)开发新的靶向药物组合（不含化疗），影响信号转导和促生存因子，作为最佳反应后结直肠癌的潜在维持方案。3)在转移性结直肠癌患者中对Specific Aims 1和2中制定的方案进行临床试验，结合详细的药理学、生物学和影像学研究，评估药物暴露、生物学效应和患者获益之间的关系。这些具体目标反映了首席研究员的兴趣和专业领域，并展示了本提案将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方面的培训，首席研究员将继续在发育治疗学方面进行培训和指导计划，该计划将利用上述特定目标和重点课程作为促进研究员和初级教师在疾病导向的临床和转化癌症研究方面的职业发展的手段。

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.