Exploiting Angiogenesis for Induction of Tumor Dormancy

描述（由申请人提供）：我们做了什么：在当前的资助期内，我们开发了一种创新的治疗方法来诱导肿瘤的慢性休眠状态。它包括将持续的低剂量化疗（称为“节拍”剂量/计划）与分子靶向抗血管生成药物（如抗vegf受体抗体）相结合。这一治疗理念已迅速进入临床试验阶段，可能会改变目前化疗治疗的一些主流模式，并使目前被认为无法使用化疗治疗的各种癌症对这些药物敏感，但在某种程度上避免了通常与标准化疗相关的更急性和严重的副作用。我们接下来要做的是：这个修订后的更新申请旨在解决一些关于抗血管生成节律化疗机制的基本问题，这些问题的答案可能对提高其抗肿瘤效果、未来临床试验的设计以及更好地理解血管生成在肿瘤休眠中的作用产生重大影响。其中包括：1)为什么低剂量节律化疗似乎对活化的内皮细胞有选择性，而不损害其他类型的正常分裂细胞，在这方面，内源性抑制剂血栓反应蛋白- 1的潜在机制诱导？如何确定特定药物和药物组合的最佳低剂量？Iii)该治疗策略对晚期（高容量）、耐药、转移性疾病是否有效？Iv)随着时间的推移，什么机制可能会损害抗血管生成治疗的疗效，如何才能显著延缓复发？意义：提出的基础研究项目具有重大转化影响的概率高，乐。，以影响实施，并指导设计，未来的临床试验测试的节拍器抗血管生成治疗的概念。它也有可能揭示对抗血管生成治疗的反应与耐药的基础，肿瘤微环境的变化（如缺氧）如何改变对抗血管生成药物的反应，并指出将各种分子靶向治疗与常规化疗药物结合的新途径，从而在不牺牲生活质量的情况下显著延长生存期。

DESCRIPTION (provided by applicant): What We Did: During the current grant period we developed an innovative therapeutic approach to induce chronic states of tumor dormancy. It consists of integrating continuous low-dose chemotherapy (called "metronomic" dosing/scheduling) with molecular targeted antiangiogenic agents such as anti-VEGF receptor antibodies. This treatment concept, which has moved rapidly into clinical trial testing, may have the potential to change some of the prevailing paradigms of chemotherapy treatment, and to render various cancers currently considered untreatable using chemotherapy, susceptible to such drugs, but in a way that avoids the more acute and serious side effects generally associated with standard chemotherapy. What We Want To Do Next: This revised renewal application is designed to address a number of fundamental questions regarding mechanisms of antiangiogenic metronomic chemotherapy, answers to which could have a significant impact on improving its anti-tumor effects, the design of future clinical trials, as well as achieving a better understanding of the role of angiogenesis in tumor dormancy. These include: i) why does low dose metronomic chemotherapy appear to be selective for activated endothelial cells and not damage other types of normal dividing cells, and, in this regard, is an underlying mechanism induction of the endogenous inhibitor, thrombospondin-l? ii) how can optimum low-doses of particular drugs and drug combinations be determined? iii) does the treatment strategy have efficacy on advanced (high volume), drug resistant, metastatic disease?; iv) what mechanisms might compromise the efficacy of metronomic antiangiogenic therapies over time, and how can relapses be significantly delayed? Significance: The proposed basic research program has a high probability of significant translational impact, Le., to influence the implementation, and guide the design, of future clinical trials testing the metronomic antiangiogenic therapy concept. It also has the potential to uncover the basis of response versus resistance to antiangiogenic therapies, how tumor microenvironmental changes, e.g. hypoxia can alter response to antiangiogenic drugs, and point out new ways of integrating various molecular targeted therapies with conventional chemotherapeutic drugs so as to significantly enhance prolongation of survival without sacrificing quality of life.