Exploiting Angiogenesis for Induction of Tumor Dormancy

描述(申请人提供)：我们所做的：在当前的赠款期间，我们开发了一种创新的治疗方法，以诱导肿瘤的长期休眠状态。它包括将持续低剂量化疗(称为节律剂量/计划)与分子靶向抗血管生成药物(如抗血管内皮生长因子受体抗体)相结合。这一治疗概念已经迅速进入临床试验测试，可能会改变一些流行的化疗治疗范例，并使目前被认为无法使用化疗治疗的各种癌症变得对这些药物敏感，但以一种避免通常与标准化疗相关的更严重和更严重的副作用的方式。我们下一步要做的是：这项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，对这些问题的回答可能会对提高其抗肿瘤效果、设计未来的临床试验以及更好地了解血管生成在肿瘤休眠中的作用产生重大影响。这些问题包括：i)为什么小剂量节律化疗似乎对激活的内皮细胞具有选择性，而不损害其他类型的正常分裂细胞，在这方面，内源性抑制物血栓反应蛋白-L的潜在机制是诱导的吗？二)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(大容量)、耐药、转移性疾病是否有效？iv)随着时间的推移，什么机制可能影响节律抗血管生成疗法的疗效，以及如何显著延缓复发？意义：拟议的基础研究计划很有可能产生重大的翻译影响，Le.，以影响未来临床试验的实施，并指导设计，测试节律抗血管生成治疗的概念。它还有可能揭示抗血管生成治疗的反应与耐药的基础，揭示肿瘤微环境的变化，如缺氧如何改变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相结合的新方法，从而在不牺牲生活质量的情况下显著延长生存时间。

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.