Enhancing Radiation Therapy: Vascular Targeting Agents

描述（由申请人提供）： 虽然放射治疗是癌症管理的主要手段，但大量以治愈为目的的放射治疗患者最终仍然失败。改善癌症治疗的传统方法主要集中在实现增加的肿瘤细胞杀伤。然而，在过去的十年里，出现了另一种治疗方法。该策略旨在通过靶向肿瘤血管网络来损害肿瘤的营养支持系统。这种“血管靶向”方法基于这样的认识，即持续扩张的脉管系统是肿瘤起始、进展和转移的基本要求。血管阻断剂（VDA）旨在引起肿瘤中快速和选择性的血管关闭。由此产生的局部缺血产生快速和广泛的肿瘤细胞杀伤。一个主要的焦点是可逆地结合微管蛋白和防止微管组装的代理。已显示用此类VDA治疗可在多种肿瘤模型中导致广泛的肿瘤坏死，并与常规抗癌治疗（包括放疗）产生协同相互作用。后者归因于这些药物选择性破坏肿瘤中心区域的能力，这些区域被广泛认为含有对细胞毒性疗法具有抗性的细胞群。主要VDA现已进入临床试验，但有关其成功应用的新问题已经出现。本研究计划中要解决的问题之一是，考虑改善VDA治疗相关高血压的步骤是否实际上可能损害这些药物的抗肿瘤疗效。其次，我们将检查使用接近临床可达到的剂量获得的病理生理学信息的知识是否允许优化剂量安排和药物递送，从而获得上级抗肿瘤疗效。本研究提案的最后一个方面将探索利用VDA治疗诱导的循环内皮祖细胞动员的定量作为VDA活性的潜在生物标志物的潜力。研究将用目前的微管蛋白结合VDA CA 4P及其有前途的第二代类似物OXi 4503进行，OXi 4503也已进入患者试验。我们相信，拟议的临床前研究将产生关键的见解所提出的问题，并提供有价值的指导方针/建议，为未来的临床VDA计划在肿瘤学。 公共卫生相关性： 这些研究的中心目标是检查应用血管靶向策略来改善癌症治疗的潜力。实验旨在研究如何提供这种疗法以获得最大的抗肿瘤疗效，以及确定开发其治疗反应的预测指标的潜力。

DESCRIPTION (provided by applicant): Although radiation therapy is a mainstay of cancer management, significant numbers of radiotherapy patients treated with curative intent still ultimately fail. Traditional methods of improving cancer therapy have focused primarily on achieving increased tumor cell kill. However, over the last decade another treatment approach has emerged. This strategy aims to impair the tumor's nutritional support system by target the tumor blood vessel network. Such "Vascular Targeting" approaches are based on the recognition that a continuously expanding vasculature is an essential requirement for tumor initiation, progression and metastasis. Vascular Disrupting Agents (VDAs) are designed to cause a rapid and selective vascular shutdown in tumors. The resulting ischemia produces rapid and extensive tumor cell kill. A main focus has been on agents that reversibly bind with tubulin and prevent microtubule assembly. Treatment with such VDAs has been shown to lead to extensive tumor necrosis in a wide variety of tumor models and to synergistic interactions with conventional anticancer treatments including radiotherapy. The latter has been attributed to the ability of these agents to selectively destroy central regions of tumors, areas widely believed to contain cell populations resistant to cytotoxic therapies. Lead VDAs have now entered clinical trials but new questions regarding their successful application have arisen. One of the issues to be addressed in this research program is whether the steps considered to ameliorate VDA-treatment associated hypertension might actually compromise the antitumor efficacy of these agents. Secondly we will examine whether knowledge of pathophysiologic information obtained using doses closer to those attainable in the clinic will allow the optimization of dose scheduling and drug delivery, leading to superior antitumor efficacy. The final aspect of this research proposal will explore the potential of utilizing the quantification of VDA treatment induced mobilization of circulating endothelial progenitor cells as potential biomarkers of VDA activity. Studies will be carried out with the current lead tubulin binding VDA CA4P and its promising second generation analog OXi4503 which has also entered patient trials. We believe that the proposed preclinical investigations will yield critical insights to the questions posed and provide valuable guidelines/suggestions for future clinical VDA initiatives in oncology. PUBLIC HEALTH RELEVANCE: The central goal of these studies is to examine the potential of applying vascular targeting strategies to improve cancer therapy. Experiments are designed to investigate how to deliver such therapies for maximum antitumor efficacy as well as determining the potential of developing predictive indicators of their treatment response.