Enhancing Radiation Therapy: Vascular Targeting Agents

描述(申请人提供)：与实体肿瘤相关的异常血管形态、血管空间异质性和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，这些药物与放射治疗的结合可能会改善治疗结果。事实上，我们之前已经证明，将VTA与放射治疗相结合将允许这两种治疗方法在微区域水平上以互补的方式作用于肿瘤，从而全面放大放射的抗肿瘤效果。尽管显然前景看好，但关于这种新方法能否成功应用于癌症治疗的许多问题仍然存在。本申请的中心目标是对血管靶向治疗的潜在机制发展新的见解，并探索新的途径，以最大限度地发挥其治疗潜力。这项研究计划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。这一策略是基于观察到，在肿瘤外围接受VTA治疗后存活的细胞积极促进新生血管的形成，以实现从存活的边缘发生的快速再生。该计划的第三部分侧重于随着当前VTA通过早期临床试验评估取得进展，对新出现的第二代化合物进行评估。具体地说，将检查最近确定的一种主要候选类似物comretataatin的抗肿瘤效力和潜在优势。最后，基于以肿瘤新生血管为靶点的假设，我们将检查除了在原发肿瘤中的活性外，VTA是否还可以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.