Combining Anti-Angiogenesis Strategies and Radiotherapy

描述（申请人提供）：放射治疗是癌症治疗的主要手段之一。事实上，通常的临床实践将这种治疗方式与手术和化疗结合起来，成为晚期癌症的最终治疗策略。然而，尽管大量应用联合治疗方式，仍有相当数量的放疗患者以治愈为目的最终失败。虽然放疗失败的原因各不相同，但异常的肿瘤微环境、肿瘤进展和肿瘤细胞的转移性扩散被认为是主要原因。由于这些耐药因素受到肿瘤发展和维持血管网络功能的能力的影响，因此在放疗环境中应用新的血管靶向方法可能会改善治疗结果。事实上，将抑制肿瘤血管生成的策略与放射治疗相结合可以增强放射治疗的抗肿瘤作用。尽管如此，关于这种新方法在癌症治疗中的成功应用仍存在许多问题。本应用的中心目标是为血管抑制治疗的潜在机制提供新的见解，并探索最大化其治疗潜力的途径。在这个研究项目中需要解决的问题之一是肿瘤固有血管的程度是否预示着它对抗血管生成治疗的反应，即高度血管化的肿瘤是否最容易受到这种干预？其次，采用四色流式细胞分析和绿色荧光蛋白（GFP）骨髓移植模型研究循环内皮祖细胞（CEP）在肿瘤血管生成中的作用和对血管抑制治疗的反应。要检查的治疗包括针对血管内皮生长因子（VEGF）信号级联的特定方面（配体和VEGF酪氨酸激酶抑制）以及内源性血管生成抑制剂内皮抑制素的调节。前者将研究小分子靶向策略，而后者将利用骨骼肌的自我补充重组腺相关病毒（SC AAV）转导作为血管抑制蛋白递送的平台。最后，通过结合针对同一信号通路的不同点或血管生成过程的不同组成部分的治疗，探索同时干扰血管生成的多个方面将导致肿瘤更好反应的假设。最有效的血管靶向策略的能力将在分次放疗环境中进行测试，以测试其改善治疗结果的潜力。这些研究的中心目标是研究应用血管靶向策略来增强实体肿瘤对放射治疗的反应的潜力。实验旨在研究这些疗法之间相互作用的机制，并开发能够最大限度地提高这些联合治疗的抗肿瘤功效的方法。

DESCRIPTION (provided by applicant): Radiation therapy is one of the mainstays of cancer management. Indeed common clinical practice integrates this therapeutic modality with surgery and chemotherapy into definitive treatment strategies of advanced cancers. Yet despite intensive application of combined modality therapies, significant numbers of radiotherapy patients treated with curative intent ultimately fail. While reasons for radiotherapy failures vary, abnormal tumor microenvironments, tumor progression, and metastatic spread of neoplastic cells are believed to be major contributors. Since these resistance factors are affected by a tumor's ability to develop and maintain a functional blood vessel network, the application of novel vascular targeting approaches in a radiotherapy setting is likely to improve treatment outcomes. Indeed combining strategies that inhibit tumor angiogenesis with radiotherapy can amplify the antitumor effects of radiation. Still, many questions regarding the successful application of this new approach to cancer treatment remain. The central goal of the present application is to develop new insights into the underlying mechanisms of angiosuppressive therapy and to explore avenues to maximize its therapeutic potential. One of the issues to be addressed in this research program is whether the extent of a tumor's inherent vascularity predicates its response to antiangiogenic therapies, i.e. will highly vascular tumors be most susceptible to such interventions? Secondly four color flow cytometric analysis and a green fluorescent protein (GFP) bone marrow transplant model will utilized to investigate the role of circulating endothelial progenitor (CEP) cells in tumor angiogenesis and response to angiosuppressive therapy. Treatments to be examined include those directed at specific aspects of the vascular endothelial growth factor (VEGF) signaling cascade (ligand and VEGF tyrosine kinase inhibition) as well as modulation of the endogenous inhibitor of angiogenesis, endostatin. The former will examine small molecule targeting strategies while the latter will utilize a self-complimentary recombinant adeno associated virus (SC AAV) transduction of skeletal muscle as a platform for angio-suppressive protein delivery. Finally the hypothesis that simultaneously interfering with multiple aspects of angiogenesis will lead to superior responses in tumors will be explored by combining therapies targeting different points in the same signaling pathway or different components of the angiogenic process in general. The ability of the most efficacious vessel targeting strategy will then be tested in a fractionated radiotherapy setting to test its potential to improve treatment outcomes. The central goal of these studies is to examine the potential of applying vascular targeting strategies to enhance the response of solid tumors to radiation therapy. Experiments are designed to investigate the mechanisms underlying the interaction between such therapies and to develop approaches that would maximize the anti-tumor efficacy of such combined treatments.