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: 10598801
• 负责人: WAFIK S. EL-DEIRY
• 金额: $ 8.68万
• 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/10598801
• 关键词: Address; Advanced Malignant Neoplasm; American; Binding; Cell Death Signaling Process; Cells; Cessation of life; Clinical; Clinical Trials; Colorectal Cancer; Data; Dopamine D2 Receptor; Dopamine Receptor; Dose; Drug Synergism; Drug resistance; Exposure to; Family; Immune; Immunization; Immunotherapy; Infiltration; Knock-out; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular Profiling; Mus; Natural Killer Cells; Neoplasm Metastasis; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Publishing; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Specimen; Stress; T-Lymphocyte; TNFRSF10B gene; TNFSF10 gene; Tumor-infiltrating immune cells; Uterine Cancer; analog; antagonist; antitumor effect; base; biological adaptation to stress; cancer stem cell; cell motility; cytokine; host neoplasm interaction; insight; leukemia/lymphoma; neoplastic cell; novel; novel therapeutics; pre-clinical; programs; receptor; resistance mechanism; small molecule; targeted treatment; tumor; tumor microenvironment

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. 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问题，这可以说是最重要的 晚期癌症患者面临的重要问题。虽然已经取得了进步 有针对性的疗法和免疫疗法，2018年将因癌症而死亡60万名美国人。超过 在过去的二十年中，我们发现了Trail受体DR5和癌症中的阻力机制， 确定了药物协同作用，并发现小分子ONC201是一流的步道 途径诱导者。基于ONC201的新颖性，其新兴的作用机理，特定 我的实验室可能对该领域和患者产生影响，该提案将重点放在Onc201上 临床前机械方向。 ONC201已作为单一疗法发展为多个 具有各种肿瘤类型的临床试验。我们的研究正在提供重要的基本信息 关于ONC201的作用机理，涉及双重封锁之后的跟踪感应 ERK和AKT在FOXO3A上融合以激活步道，以及一个集成的应力响应， 涉及EIF2-Alpha依赖性ATF4/CHOP介导的TRAIL死亡受体5的诱导。 ONC201耗尽了结直肠癌干细胞，并在小鼠中剂量强化我们观察到 NK和T细胞浸润到处理的 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进行临床给药。我们的具体目的包括：目标＃1：调查ONC201 通过NK和T细胞对肿瘤微环境的影响，导致抗肿瘤和抗 转移效应。 AIM＃2：研究ONC201的直接结合目标的作用， 多巴胺受体DRD2/DRD3的亚家族介导其抗肿瘤作用。我们将探索 假定的特异性药物结合靶标多巴胺的拮抗作用之间的新连接 受体D2和D3，onc201触发的小径和集成的应力途径机制， 它们在正常与肿瘤细胞中的状态，以及患者的敏感细胞或耐抗性细胞或肿瘤 暴露于ONC201。我们的研究包括对免疫刺激的深度机理分析 ONC201的影响，包括分析不同免疫细胞亚群的免疫浸润， 涉及吸引免疫细胞或可能是潜在的细胞的各种细胞因子 免疫抑制，使用TRAIL和DR5淘汰以及NCR1-GFP小鼠的使用 GFP（+）NK细胞分析已处理的ONC201（或ONC201模拟）的宿主肿瘤相互作用 肿瘤。我们通过肿瘤的分子分析探索ONC201的电阻机制 来自ONC201试验的标本并批判性地评估了其在临床前模型中的作用。