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

项目总结 该项目解决了癌症的耐药性问题，这是可以说是最重要的 晚期癌症患者面临的问题。虽然靶向治疗取得了进展，但 根据免疫疗法，2018年将有60多万美国人死于癌症。在过去的二十年里，我们 发现肿瘤中TRAIL受体DR5和耐药机制，确定药物协同作用，以及 发现小分子ONC201是一种一流的TRAIL途径诱导剂。基于的新颖性 ONC201，它的新兴作用机制，我的实验室可以对该领域和 患者，这项建议将深入关注ONC201临床前机制方向。ONC201已经 作为一种单一疗法，进展为各种肿瘤类型的多个临床试验。我们的研究是 为ONC201参与TRAIL的作用机制提供重要的基础信息 ERK和Akt双阻断后诱导融合于Foxo3a激活TRAIL，并整合 依赖eIF2-α的ATF4/CHOP介导的诱导TRAIL死亡的应激反应 受体5.ONC201耗尽小鼠结直肠癌干细胞并随剂量增加 观察抗肿瘤转移、抑制细胞迁移和NK、T细胞在治疗后的侵袭作用 肿瘤(最近由Wagner等人发表，J.Clin。投资，2018年)。我们的数据导致了 所有公开临床试验中的临床剂量，包括福克斯·蔡斯癌症中心(NCT02609230)。我们的 具体目标包括：目标1：研究ONC201通过NK对肿瘤微环境的影响 和T细胞具有抗肿瘤和抗转移的作用。目标2：调查即刻事件的作用 多巴胺受体DRD2/DRD3亚家族ONC201的结合靶点 肿瘤效应。我们将探索推测的特定药物之间的拮抗作用之间的新联系 靶向多巴胺受体D2和D3结合、TRAIL和整合应激途径机制 由ONC201触发，它们在正常细胞与肿瘤细胞、敏感细胞与耐药细胞或肿瘤中的状态 接触ONC201的患者。我们的研究包括对免疫机制的深入分析。 ONC201的刺激作用，包括分析不同免疫细胞亚群的免疫渗透， 各种细胞因子参与将免疫细胞吸引到肿瘤或那些可能具有免疫力的肿瘤- 抑制，并使用TRAIL和DR5基因敲除以及带有GFP()NK细胞的NCR1-GFP小鼠 分析ONC201(或ONC201类似物)治疗的肿瘤与宿主肿瘤的相互作用。我们探索ONC201 通过ONC201试验和危重病例肿瘤标本的分子图谱研究耐药机制 评估它们在临床前模型中的作用。

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.