Combination Strategies for Angiogenesis Inhibition

描述（由申请人提供）：该提案描述了一个5年计划，其中候选人将完成培训，成为一名独立的临床研究者，专注于血管生成抑制剂作为癌症治疗药物。 在他的奖学金和第一年作为医学肿瘤学教师的过程中，Flaherty博士在申办者O'Dwyer博士的监督下，获得了设计和进行研究药物早期临床试验的经验。 Flaherty博士撰写的研究建立了他协调多学科努力的能力，以了解实验性靶向治疗的作用机制和耐药性。 该奖项将使Flaherty博士完成以患者为导向的研究硕士学位。 在拟议的项目过程中，Flaherty博士将进行一系列临床试验，以进一步了解血管生成抑制剂在实体瘤治疗中的用途。 到5年期结束时，Flaherty博士将能够竞争同行评审的资金，以扩大这些发现。 有大量的临床前数据表明，将VEGF信号传导抑制剂与靶向其他血管生成介质的药物组合导致血管生成的协同抑制。 该项目的主要假设是，有效抑制血管生成将需要靶向内皮细胞和周细胞中的关键信号介质的组合剂。 为此，我们提出了一系列的临床试验相结合的研究药物针对参与血管生成的信号通路。 这些组合是基于VEGF抑制剂与PDGF受体、EGF受体和Raf酪氨酸激酶抑制剂的配对。 我们建议在用所提出的抗血管生成方案治疗之前表征肿瘤微血管，目的是鉴定与治疗益处强烈相关的标记物。 我们还建议评估动态对比增强MRI和多普勒超声作为模式，以确定在治疗过程中的早期点，哪些患者可能获得长期的临床受益。 博士Flaherty的导师O'Dwyer博士是宾夕法尼亚大学癌症中心发展治疗项目的主任。 他是研究治疗领域公认的领导者，有指导成功临床研究人员的记录，并致力于Flaherty博士的培训。

DESCRIPTION (provided by applicant): The proposal describes a 5-year plan wherein the candidate will complete his training to be an independent clinical investigator with a focus on inhibitors of angiogenesis as cancer therapeutics. During the course of his fellowship and first year as faculty in Medical Oncology, Dr. Flaherty has gained experience in the design and conduct of early phase clinical trials with investigational agents under the supervision of the sponsor, Dr. O'Dwyer. The studies that Dr. Flaherty has authored establish his ability to coordinate a multidisciplinary effort to understand the mechanisms of action and resistance for experimental targeted therapies. This award will allow Dr. Flaherty to complete a Master's Degree in Patient Oriented Research. During the course of the proposed project Dr. Flaherty will conduct a series of clinical trials that will further the understanding of the use of inhibitors of angiogenesis in the treatment of solid tumors. By the end of the 5-year period, Dr. Flaherty will be in a position to compete for peer-reviewed funding to extend these findings. There are substantial preclinical data to suggest that combining VEGF signaling inhibitors with agents that target other mediators of angiogenesis results in synergistic inhibition of angiogenesis. The principal hypothesis of the project is that effective inhibition of angiogenesis will require combining agents that target critical signaling mediators in endothelial cells and pericytes. To this end, we propose a series of clinical trials combining investigational agents targeted against signaling pathways involved in angiogenesis. These combinations are based on the pairing of a VEGF inhibitor with inhibitors of the PDGF receptor, EGF receptor, and Raf tyrosine kinases. We propose to characterize tumor microvasculature prior to treatment with the proposed anti-angiogenesis regimens with the purpose of identifying markers that are strongly correlated with therapeutic benefit. We also propose to evaluate dynamic contrast-enhanced MRI and Doppler ultrasound as modalities to identify, at an early point in the treatment course, which patients are likely to attain prolonged clinical benefit. Dr. Flaherty's mentor, Dr. O'Dwyer, is director of the Developmental Therapeutics Program at the University of Pennsylvania Cancer Center. He is a recognized leader in the field of investigational therapies, has a record of mentoring successful clinical researchers, and is committed to Dr. Flaherty's training.