IDO Inhibitors for Combinatorial Cancer Therapy

描述（由申请人提供）：背景。非常需要改进的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。癌症用于逃避免疫的一种机制是通过免疫抑制酶IDO（吲哚胺2，3-双加氧酶）的活化介导的，其限制细胞毒性T细胞的活化。我们通过Bin 1的遗传控制鉴定了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。小鼠基因敲除研究将Bin 1丢失与恶性能力增加联系起来，部分通过IDO介导的免疫逃避。如果Bin 1或其他肿瘤抑制因子中的病变通过升高IDO而促进免疫逃避，则预测IDO活性的小分子抑制剂将促进肿瘤细胞的免疫排斥。指导假设和具体目标：初步研究表明，生物活性IDO抑制剂与细胞毒性化疗药物的组合在乳腺癌转基因小鼠模型（MMTVneu小鼠）中引发大量肿瘤细胞死亡和消退，其中单一药剂无效。IDO抑制剂在体外没有细胞毒性，因此它们的抗肿瘤活性不会通过传统的体外药物筛选来揭示。在目标1中，我们将改变IDO抑制剂的给药和时间表以优化功效。在目的2和3中，我们将合成并测定已经鉴定的四个系列的IDO抑制剂中的化合物的酶抑制活性。最后，在目标4和5中，将检查先导化合物的药理学和功效。 我们的长期目标是为这种新的治疗策略的临床开发奠定基础。创新和意义：提出了几项创新。最普遍的创新是未探索的概念，即通过结合免疫疗法和细胞毒性化疗可以增强癌症治疗。IDO的生物化学已经很发达，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方式，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重要性。IDO作为癌症药物靶标具有吸引人的特征，包括其药理学易处理性、其缺乏基因组相关物以及其容易的药效学测量。该应用程序提供了一个独特的机会，以获得对癌症病理生理学和治疗的创新观点。

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.