Enhancing Radiation Therapy: Vascular Targeting Agents

描述(由申请人提供)： 虽然放射治疗是癌症治疗的支柱，但相当数量的放射治疗患者的治疗意图仍然最终失败。改善癌症治疗的传统方法主要集中在实现更高的肿瘤细胞杀伤率。然而，在过去的十年里，出现了另一种治疗方法。这一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”的方法是基于这样一种认识，即不断扩张的血管系统是肿瘤发生、发展和转移的基本要求。血管干扰剂(VDA)的设计目的是在肿瘤中导致快速和选择性的血管关闭。由此产生的缺血会迅速而广泛地杀死肿瘤细胞。一个主要的焦点一直是可逆地与微管蛋白结合并阻止微管组装的药物。这种VDA的治疗已被证明在各种肿瘤模型中导致广泛的肿瘤坏死，并与包括放射治疗在内的传统抗癌治疗产生协同作用。后者被归因于这些药物选择性地摧毁肿瘤中心区域的能力，人们普遍认为这些区域包含对细胞毒治疗具有抗药性的细胞群体。铅VDA现在已进入临床试验，但关于其成功应用的新问题已经出现。这项研究计划要解决的问题之一是，被考虑的改善VDA治疗相关高血压的步骤是否真的会损害这些药物的抗肿瘤效果。其次，我们将研究使用与临床可获得的剂量更接近的剂量获得的病理生理信息知识是否有助于优化剂量安排和药物输送，从而产生更好的抗肿瘤疗效。这项研究计划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作为VDA活性的潜在生物标志物的可能性。目前的铅微管蛋白结合VDA CA4P及其前景看好的第二代类似物Oxi4503将进行研究，该类似物也已进入患者试验。我们相信，拟议的临床前调查将为所提出的问题提供关键的见解，并为肿瘤学中未来的临床VDA倡议提供有价值的指导/建议。 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。实验旨在调查如何提供这种疗法以获得最大的抗肿瘤疗效，并确定开发其治疗反应预测指标的潜力。

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.