Combination Strategies for Angiogenesis Inhibition

描述(由申请人提供)：该提案描述了一项为期5年的计划，在该计划中，候选人将完成他的培训，成为一名独立的临床调查员，专注于血管生成抑制剂作为癌症治疗药物。在担任医学肿瘤学教授的第一年期间，Flaherty博士在赞助商O‘Dwyer博士的监督下，与研究人员一起设计和实施早期临床试验，积累了经验。弗莱厄蒂博士撰写的研究表明，他有能力协调多学科的努力，以了解实验性靶向治疗的作用机制和耐药性。这一奖项将允许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，以加深对血管生成抑制剂在实体肿瘤治疗中的使用的理解。到5年结束时，弗莱厄蒂博士将有能力争取同行评审的资金，以扩大这些研究结果。 大量临床前数据表明，将血管内皮生长因子信号转导抑制剂与靶向其他血管生成介质的药物相结合，可协同抑制血管生成。该项目的主要假设是，有效地抑制血管生成将需要针对内皮细胞和周细胞中的关键信号媒介的联合药物。为此，我们提出了一系列临床试验，结合针对涉及血管生成的信号通路的研究药物。这些组合是基于一种血管内皮生长因子抑制剂与PDGF受体、EGF受体和Raf酪氨酸激酶的抑制剂配对。我们建议在使用建议的抗血管生成方案进行治疗前对肿瘤微血管进行表征，以确定与治疗效果密切相关的标志物。我们还建议评估动态增强MRI和多普勒超声，作为在治疗过程的早期确定哪些患者可能获得长期临床益处的方法。 弗莱厄蒂博士的导师奥德怀尔博士是宾夕法尼亚大学癌症中心发展治疗项目的主任。他是研究疗法领域公认的领导者，有指导成功的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.