IDO Inhibitors for Combinatorial Cancer Therapy

用于组合癌症治疗的 IDO 抑制剂

• 批准号: 7027648
• 负责人: GEORGE C PRENDERGAST
• 金额: $ 27.52万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027648
• 关键词: breast neoplasms; chemical synthesis; combination cancer therapy; disease /disorder model; drug discovery /isolation; drug screening /evaluation; enzyme activity; genetically modified animals; laboratory mouse; mouse mammary tumor virus; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; oxidoreductase inhibitor; paclitaxel; pharmacokinetics; tryptophan 2,3 dioxygenase

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.

描述（由申请人提供）：背景。非常需要改进策略来消除全身性癌症。鉴于癌症中普遍存在免疫逃避，免疫干预可能有用。癌症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）的激活介导，该酶限制细胞毒性 T 细胞的激活。我们通过 Bin 1（一种在乳腺癌和其他癌症中通常减弱的肿瘤抑制因子）的基因控制来识别 IDO。小鼠敲除研究将 Bin 1 缺失与恶性能力增加联系起来，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中的病变通过提高 IDO 来促进免疫逃避，那么 IDO 活性的小分子抑制剂将有望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可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，而单药无效。 IDO抑制剂在体外没有细胞毒性，因此传统的体外药物筛选无法揭示其抗肿瘤活性。在目标 1 中，我们将改变 IDO 抑制剂的剂量和时间安排以优化疗效。在目标2和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 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治疗策略的临床开发奠定基础。创新和意义：提供了多项创新。最普遍的创新是未经探索的概念，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 的生物化学已经很成熟，但它在癌症中的病理生理学作用实际上尚未被探索：IDO 的小分子抑制剂为癌症治疗提供了新的方式，并且它们为化学遗传学提供了工具来确定 IDO 对肿瘤免疫和生存的重要性。 IDO 作为癌症药物靶点具有吸引人的特点，包括其药理学易处理性、缺乏基因组相关性以及易于药效测量。该应用程序提供了获得癌症病理生理学和治疗创新视角的独特机会。