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

项目摘要 该项目致力于解决癌症耐药性问题，这可以说是最重要的 晚期癌症患者面临的问题。虽然在靶向治疗方面取得了进展， 免疫疗法，2018年将有超过60万美国人死于癌症。在过去的二十年里，我们 发现了TRAIL受体DR5和癌症的耐药机制，确定了药物协同作用， 发现了小分子ONC201作为一流的TRAIL通路诱导剂。基于对 ONC201，它的新兴作用机制，我的实验室对该领域的具体影响， 患者，该提案将深入关注ONC201临床前机制方向。ONC201具有 作为单药治疗进展到多种肿瘤类型的多项临床试验中。我们的研究是 提供了关于涉及TRAIL的ONC201作用机制的重要基础信息 在双重阻断ERK和Akt会聚在Foxo3a上以激活TRAIL后的诱导，以及整合的 涉及eIF2-α依赖性ATF4/CHOP介导的TRAIL死亡诱导的应激反应 受体5。ONC201消耗结直肠癌干细胞，并在小鼠中加强剂量， 观察到的抗转移作用、细胞迁移的抑制以及NK和T细胞向处理的细胞中的浸润。 肿瘤（最近由瓦格纳等人，J. Clin. Invest.，2018年）。我们的数据导致了 在包括Fox Chase癌症中心（NCT 02609230）的所有开放临床试验中的临床给药。我们 具体目标包括：目标#1：研究ONC201通过NK细胞对肿瘤微环境的影响 和T细胞，导致抗肿瘤和抗转移作用。目标#2：调查直接的作用 多巴胺受体DRD 2/DRD 3亚家族ONC201的结合靶点，介导其抗- 肿瘤效应我们将探索推定的特异性药物的拮抗作用之间的新联系， 结合靶多巴胺受体D2和D3、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中的状态，以及敏感细胞与耐药细胞或肿瘤中的状态， 暴露于ONC201的患者。我们的研究包括免疫的深入机制分析 ONC201的刺激作用，包括分析不同免疫细胞亚群的免疫浸润， 参与将免疫细胞吸引到肿瘤或那些可能具有潜在免疫性的细胞因子的各种细胞因子， 抑制性，以及使用TRAIL和DR5敲除以及具有GFP（+）NK细胞的NCR1-GFP小鼠， 分析ONC201（或ONC201类似物）处理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谱分析， 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.