Enhancing Radiation Therapy: Vascular Targeting Agents

增强放射治疗：血管靶向剂

• 批准号: 7035767
• 负责人: DIETMAR W SIEMANN
• 金额: $ 29.07万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035767
• 关键词: angiogenesis; angiogenesis inhibitors; antineoplastics; athymic mouse; combination cancer therapy; drug screening /evaluation; metastasis; neoplasm /cancer blood supply; neoplasm /cancer radiation therapy; nonhuman therapy evaluation

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.

描述（由申请人提供）：与实体瘤相关的异常血管形态，血管异质性以及与实体瘤相关的代谢微环境是导致放射治疗损失的主要因素。由于所有这些都可能受血管靶向剂（VTA）的治疗影响，因此这种放射疗法的组合可能会改善治疗结果。确实，我们以前已经表明，将VTA与放射疗法结合起来，可以使两种治疗在微区域水平的肿瘤中以互补的方式起作用，从而导致辐射的抗肿瘤作用的总体扩增。尽管显然很有希望，但有关这种新方法在癌症治疗中成功应用的许多问题仍然存在。本应用的核心目标是开发新的见解，以了解血管靶向疗法的潜在机制，并探索新的途径以最大程度地发挥其治疗潜力。该研究计划中要解决的问题之一是，剂量的剂量是否比通常在临床上使用的剂量低，但是接近诊所可达到的剂量，VTA的辐射反应增强仍然是可行的。其次，我们建议检查VTA后治疗条件是否为抗血管生成疗法的应用提供了有利的环境。该策略基于这样的观察结果，即在肿瘤周围生存的VTA治疗的细胞积极促进新血管形成，以实现从可行的边缘产生的快速再生。随着当前VTA通过早期临床试验评估，该程序的第三个组成部分集中于对新兴第二代化合物的评估。将检查最近确定的Combretastatin的铅候选类似物的抗肿瘤效力和潜在优势。最后，基于以下假设：靶向肿瘤新生血管系统应具有通过已建立的血管网络诱导所有肿瘤反应的可能性，我们将检查是否除了在原发性肿瘤中的活性外，VTA还会影响转移性疾病的管理。