ONC201/TIC10 Anti-tumor Effect Through Regulation of the TRAIL pathway

ONC201/TIC10 通过调节 TRAIL 通路发挥抗肿瘤作用

• 批准号: 9924502
• 负责人: WAFIK S. EL-DEIRY
• 金额: $ 48.51万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924502
• 关键词: Address; Advanced Malignant Neoplasm; American; Antitumor Response; Apoptotic; Binding; CXCL10 gene; Cell Death; Cell Death Signaling Process; Cell Survival; Cells; Cessation of life; Clinical; Clinical Data; Clinical Trials; Colorectal Cancer; Combination Drug Therapy; Cytotoxic T-Lymphocytes; DRD1 gene; DRD2 gene; DRD5 gene; Data; Dopamine Antagonists; Dopamine D2 Receptor; Dopamine Receptor; Dose; Drug Synergism; Drug resistance; Epigenetic Process; Exposure to; Family; Fibroblasts; Fox Chase Cancer Center; Goals; Growth; Immune; Immune response; Immunization; Immunotherapy; Infiltration; Knock-out; Knockout Mice; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular Profiling; Mus; Mutation; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patient Monitoring; Patients; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Publications; Publishing; Radiation therapy; Regulation; Research; Resistance; Role; Screening for cancer; Signal Pathway; Signal Transduction; Specimen; Stress; Subgroup; T-Cell Activation; T-Lymphocyte; TNFRSF10B gene; TNFSF10 gene; Therapeutic; Translating; Tumor Tissue; Tumor-infiltrating immune cells; Uterine Cancer; analog; anti-PD1 therapy; antitumor effect; base; biological adaptation to stress; cancer prevention; cancer stem cell; cancer therapy; cell motility; cell type; combinatorial; cytokine; cytotoxic; first-in-human; host neoplasm interaction; human study; in vivo; insight; leukemia/lymphoma; neoplastic cell; novel; novel strategies; novel therapeutics; patient response; pre-clinical; programs; receptor; receptor binding; recruit; resistance mechanism; small molecule; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor progression; tumor specificity

PROJECT SUMMARY The project addresses the problem of drug resistance in cancer which is arguably the most important problem facing patients with advanced cancer. While advances have been made in targeted therapy and immunotherapy, over 600,000 Americans will die in 2018 from cancer. Over the last two decades, we discovered TRAIL receptor DR5 and resistance mechanisms in cancer, identified drug synergies, and discovered small molecule ONC201 as a first-in-class TRAIL pathway inducer. Based on the novelty of ONC201, its emerging mechanism of action, the specific impact my lab can have on the field and on patients, this proposal will focus in depth on ONC201 preclinical mechanistic directions. ONC201 has progressed as a monotherapy into multiple clinical trials with various tumor types. Our studies are providing important basic information regarding the mechanism of action of ONC201 involving TRAIL induction after dual blockade of ERK and Akt converging on Foxo3a to activate TRAIL, and an integrated stress response that involves eIF2-alpha dependent ATF4/CHOP-mediated induction of TRAIL death receptor 5. ONC201 depletes colorectal cancer stem cells and with dose intensification in mice we observed anti-metastasis effects, inhibition of cell migration, and infiltration by NK and T cells into treated tumors (recently published by Wagner et al., J. Clin. Invest., 2018). Our data has led to a change in clinical dosing in all open clinical trials including at Fox Chase Cancer Center (NCT02609230). Our specific aims include: Aim #1: Investigate ONC201 effects on the tumor microenvironment through NK and T cells leading to anti-tumor and anti-metastasis effects. Aim #2: Investigate the role of the immediate binding target for ONC201, the sub-family of dopamine receptors DRD2/DRD3, in mediating its anti- tumor effects. We will explore novel connections between antagonism of the putative specific drug binding target dopamine receptor D2 and D3, the TRAIL and integrated stress pathway mechanism triggered by ONC201, their status in normal vs tumor cells, and sensitive vs resistant cells or tumors from patients exposed to ONC201. Our studies include in depth mechanism analysis of the immune stimulatory effects of ONC201, including analysis of immune infiltration by different immune cell subsets, various cytokines involved in attracting immune cells to tumors or those that may be potentially immune- suppressive, and use of TRAIL and DR5 knockout as well as NCR1-GFP mice with GFP(+) NK cells to analyze host tumor interactions of ONC201 (or ONC201 analogue) treated tumors. We explore ONC201 resistance mechanisms through molecular profiling of tumor specimens from ONC201 trials and critically assess their role in preclinical models.

项目摘要 该项目解决了癌症中耐药性的问题，这可以说是最重要的 晚期癌症患者面临的问题。虽然在有针对性的疗法和 免疫疗法，超过60万美国人将因癌症死亡。在过去的二十年中，我们 发现了癌症中发现的TRAIL受体DR5和耐药机制，确定的药物协同作用和 发现小分子ONC201是一流的步道途径诱导剂。基于新奇 Onc201，其新兴的作用机理，我的实验室可能对现场和范围产生的具体影响 患者，该提案将重点放在ONC201临床前机械方向上。 Onc201有 作为一种单一疗法发展为多种肿瘤类型的多个临床试验。我们的研究是 提供有关涉及TRAIL的ONC201行动机制的重要基本信息 双重封锁ERK和AKT在FOXO3A上汇聚以激活步道后的感应，并集成了 涉及EIF2-Alpha依赖性ATF4/CHOP介导的Trail Trail Death的压力反应 受体5。ONC201耗尽结直肠癌干细胞和小鼠的剂量加强 观察到的抗促作用，细胞迁移的抑制以及NK和T细胞浸润 肿瘤（最近由Wagner等人，J。Clin。Invest。，2018年出版）。我们的数据导致了变化 在所有开放临床试验中，包括Fox Chase Cancer Center（NCT02609230）的临床剂量。我们的 具体目的包括：目标＃1：通过NK调查ONC201对肿瘤微环境的影响 和T细胞导致抗肿瘤和抗雷达作用。目标＃2：调查即时的作用 结合了ONC201，多巴胺受体DRD2/DRD3的亚家族的结合靶 肿瘤效应。我们将探索推定特定药物的拮抗作用之间的新颖联系 结合靶标多巴胺受体D2和D3，小径和集成的应力途径机制 由ONC201触发，在正常肿瘤细胞中的状态以及敏感的抗性细胞或肿瘤 暴露于ONC201的患者。我们的研究包括对免疫的深度机理分析 ONC201的刺激作用，包括分析不同免疫细胞亚群免疫浸润的分析， 涉及吸引免疫细胞或可能具有免疫的各种细胞因子 抑制和使用TRAIL和DR5敲除以及具有GFP（+）NK细胞的NCR1-GFP小鼠 分析是ONC201（或ONC201类似物）治疗的肿瘤的宿主肿瘤相互作用。我们探索ONC201 通过来自ONC201试验的肿瘤标本的分子分析和批判性的耐药性机制 评估它们在临床前模型中的作用。