Enhancing Radiation Therapy: Vascular Targeting Agents

描述（由申请方提供）：异常血管形态、血管空间异质性和与实体瘤相关的代谢微环境是导致放射治疗失败的主要因素。由于所有这些都可能受到血管靶向药物（VTA）治疗的影响，因此这些药物与放射治疗的组合可能会改善治疗结果。事实上，我们以前已经表明，将VTA与放射治疗相结合将允许这两种治疗在微区域水平上以互补的方式在肿瘤中起作用，从而导致辐射的抗肿瘤作用的总体放大。虽然很有希望，但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靶向治疗的潜在机制的新见解，并探索使其治疗潜力最大化的新途径。本研究计划中要解决的问题之一是，在低于临床前通常使用的剂量，但更接近临床可达到的剂量时，VTA增强辐射反应是否仍然可行。其次，我们建议检查VTA治疗后的条件是否为应用抗血管生成疗法提供了有利的环境。这种策略是基于观察到的VTA治疗中存活的细胞在肿瘤周边积极促进新血管形成，以实现从可行的边缘发生的快速再生长。该计划的第三个组成部分是集中在新出现的第二代化合物的评价，目前的VTA进展通过早期临床试验评价。具体而言，将检查最近确定的考布他汀的主要候选类似物的抗肿瘤效力和潜在优越性。最后，基于靶向肿瘤新血管系统应提供在具有已建立血管网络的所有肿瘤中诱导反应的可能性的假设，我们将研究除了它们在原发性肿瘤中的活性之外，VTA是否可以影响转移性疾病的管理。

DESCRIPTION (provided by applicant): The aberrant vascular morphology, spatial heterogeneity in vessels, and metabolic microenvironments associated with solid tumors, are major factors contributing to treatment failures in radiotherapy. Since all of these may be affected by treatment with vascular targeting agents (VTAs), the combination of such agents with radiotherapy is likely to improve treatment outcomes. Indeed, we previously have shown that combining a VTA with radiotherapy would allow the two treatments to act in a complimentary fashion in tumors at the microregional level resulting in an overall amplification of the antitumor effects of radiation. Though clearly promising, 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 vascular targeting therapy and to explore new avenues to maximize its therapeutic potential. One of the issues to be addressed in this research program is whether at lower doses than have typically be used pre-clinically, but closer to those attainable in the clinic, enhancement of radiation response by VTAs is still feasible. Secondly, we propose to examine whether post VTA treatment conditions provide a favorable setting for the application of antiangiogenic therapies. This strategy is based on the observation that cells surviving VTA treatment at the tumor periphery aggressively promote neovascularization in order to achieve the rapid regrowth that occurs from the viable rim. A third component of the program is focused on the evaluation of new emerging second generation compounds as current VTAs progress through early clinical trial evaluations. Specifically the antitumor potency and potential superiority of a recently identified lead candidate analog of combretastatin will be examined. Finally, based on the hypothesis that targeting the tumor neovasculature should offer the possibility of inducing responses in all tumors with an established vessel network, we will examine whether in addition to their activity in primary tumors, VTAs can impact the management of metastatic disease.