Combining Anti-Angiogenesis Strategies and Radiotherapy

描述（由申请人提供）：放射治疗是癌症管理的支柱之一。事实上，常见的临床实践将这种治疗方式与手术和化疗整合到晚期癌症的确定性治疗策略中。然而，尽管大量应用综合疗法，但大量以治愈为目的的放射治疗患者最终失败了。虽然放射治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扩散被认为是主要原因。由于这些抵抗因素受到肿瘤发展和维持功能性血管网络的能力的影响，因此在放射治疗环境中应用新型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然存在许多问题。本申请的中心目标是开发对血管抑制疗法的潜在机制的新见解，并探索使其治疗潜力最大化的途径。在这项研究计划中要解决的问题之一是肿瘤的固有血管分布的程度是否预示着其对抗血管生成治疗的反应，即高度血管化的肿瘤最容易受到这种干预？其次，采用四色流式细胞术和绿色荧光蛋白（GFP）骨髓移植模型研究循环内皮祖细胞（CEP）在肿瘤血管生成和血管抑制治疗中的作用。待检查的治疗包括针对血管内皮生长因子（VEGF）信号级联（配体和VEGF酪氨酸激酶抑制）的特定方面以及调节血管生成的内源性抑制剂内皮抑制素的治疗。前者将研究小分子靶向策略，而后者将利用骨骼肌的自我互补重组腺相关病毒（SC AAV）转导作为血管抑制蛋白递送的平台。最后，将通过组合靶向相同信号传导途径中的不同点或一般血管生成过程的不同组分的疗法来探索同时干扰血管生成的多个方面将导致肿瘤中的上级应答的假设。然后将在分次放疗环境中测试最有效的血管靶向策略的能力，以测试其改善治疗结局的潜力。这些研究的中心目标是检查应用血管靶向策略来增强实体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，并开发最大化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.