Enhancing Radiation Therapy: Vascular Targeting Agents

描述（由申请人提供）：与实体瘤相关的血管形态异常、血管空间异质性和代谢微环境是导致放疗失败的主要因素。由于所有这些都可能受到血管靶向药物（VTAs）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，我们之前已经表明，将VTA与放疗相结合将使这两种治疗方法在肿瘤微区域水平上以互补的方式起作用，从而使辐射的抗肿瘤效果得到全面放大。尽管前景明朗，但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对血管靶向治疗的潜在机制有新的认识，并探索新的途径来最大限度地发挥其治疗潜力。本研究项目中需要解决的问题之一是，在低于临床前通常使用的剂量，但接近临床可达到的剂量时，VTAs增强辐射反应是否仍然可行。其次，我们建议研究VTA治疗后的条件是否为抗血管生成治疗的应用提供了有利的环境。这一策略是基于这样的观察，即在肿瘤周围接受VTA治疗后存活的细胞积极促进新生血管形成，以实现可存活边缘的快速再生。该项目的第三个组成部分侧重于评估新出现的第二代化合物，通过早期临床试验评估当前VTAs的进展。特别是抗肿瘤的效力和潜在的优势，最近确定的主要候选类似物combretastatin将被检查。最后，基于靶向肿瘤新生脉管系统的假设，我们将研究除了在原发肿瘤中的活性外，VTAs是否还能影响转移性疾病的治疗。

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.