IDO Inhibitors for Combinatorial Cancer Therapy

描述（由申请人提供）：背景。我们非常需要改进策略来消除系统性癌症。鉴于免疫逃避在癌症中普遍存在，免疫干预可能是有用的。癌症用来逃避免疫的一种机制是由免疫抑制酶IDO（吲哚胺2,3 -双加氧酶）的激活介导的，IDO限制了细胞毒性T细胞的激活。我们通过Bin 1的遗传控制确定了IDO， Bin 1是一种在乳腺癌和其他癌症中通常减弱的肿瘤抑制因子。小鼠敲除研究将Bin 1缺失与恶性肿瘤能力增加联系起来，部分是通过ido介导的免疫逃避。如果Bin 1或其他肿瘤抑制因子的病变通过升高IDO来促进免疫逃避，那么可以预测IDO活性的小分子抑制剂会促进肿瘤细胞的免疫排斥。指导假设和具体目的：初步研究表明，在乳腺癌转基因小鼠模型（MMTVneu小鼠）中，生物活性IDO抑制剂与细胞毒性化疗药物联合使用可引发大量肿瘤细胞死亡和消退，其中单一药物无效。IDO抑制剂在体外不具有细胞毒性，因此其抗肿瘤活性无法通过传统的体外药物筛选显示。在目的1中，我们将改变IDO抑制剂的剂量和时间表以优化疗效。在目标2和目标3中，我们将合成并测定已鉴定的四个系列IDO抑制剂中化合物的酶抑制活性。最后，在目标4和目标5中，将对先导化合物的药理学和功效进行研究。我们的长期目标是为这种新的治疗策略的临床发展奠定基础。创新与意义：本文提出了几个创新点。最普遍的创新是一个未经探索的概念，即通过结合免疫疗法和细胞毒性化疗，癌症治疗可能会得到加强。IDO的生物化学研究很发达，但其在癌症中的病理生理作用几乎未被探索：IDO的小分子抑制剂为癌症治疗提供了一种新的模式，它们为化学遗传学提供了一种工具，以确定IDO对肿瘤免疫和生存的意义。IDO作为一种癌症药物靶点具有吸引人的特点，包括它的药理学可追溯性、缺乏基因组亲缘关系以及易于药效学测量。这个应用程序提供了一个独特的机会，以获得对癌症病理生理和治疗的创新观点。

DESCRIPTION (provided by applicant): Background. There is a great need for improved strategies to eliminate systemic cancer. Immune interventions may be useful given that immune evasion occurs universally in cancer. One mechanism cancers use to evade immunity is mediated by activation of the immunosuppressive enzyme, IDO (indoleamine 2, 3-dioxygenase), which limits activation of cytotoxic T cells. We identified IDO through its genetic control by Bin 1, a tumor suppressor commonly attenuated in breast cancers and other cancers. Mouse knockout studies link Bin 1 loss to increased malignant capacity, in part via IDO-mediated immune evasion. If lesions in Bin 1 or other tumor suppressors promote immune evasion by elevating IDO, then small molecule inhibitors of IDO activity would be predicted to promote immune rejection of tumor cells. Guiding Hypothesis and Specific Aims: Preliminary studies show that the combination of a bioactive IDO inhibitor with a cytotoxic chemotherapeutic drug triggers massive tumor cell deaths and regression in a transgenic mouse model of breast cancer (MMTVneu mice), where single agents are ineffective. IDO inhibitors are not cytotoxic in vitro, so their antitumor activity would not be revealed by traditional in vitro drug screens. In Aim 1, we will vary dosing and scheduling of an IDO inhibitor to optimize efficacy. In Aims 2 and 3, we will synthesize and assay the enzyme inhibitory activity of compounds in four series of IDO inhibitors that have been identified. Lastly, in Aims 4 and 5, the pharmacology and efficacy of lead compounds will be examined. Our long-term goal is to build a foundation for clinical development of this new therapeutic strategy. Innovation and Significance: Several innovations are offered. The most general innovation is the unexplored concept that cancer treatment might be enhanced by combining immunotherapy and cytotoxic chemotherapy. The biochemistry of IDO is well developed, but its pathophysiological role in cancer is virtually unexplored: Small molecule inhibitors of IDO provide a new modality for cancer therapy, and they offer a tool for chemical genetics to establish the significance of IDO to tumor immunity and survival. IDO has attractive features as a cancer drug target, including its pharmacological tractability, its lack of genomic relatives, and its facile pharmacodynamic measurement. This application offers a unique opportunity to gain an innovative perspective on cancer pathophysiology and treatment.