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

基本信息

批准号：
9765925
负责人：
WAFIK S. EL-DEIRY
金额：
$ 48.77万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/9765925
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 Death Receptor 5 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 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

项目摘要

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.

项目概要该项目解决了癌症的耐药性问题，这可以说是最重要的问题晚期癌症患者面临的问题。尽管靶向治疗和免疫疗法，2018 年将有超过 60 万美国人死于癌症。在过去的二十年里，我们发现了癌症中的 TRAIL 受体 DR5 和耐药机制，确定了药物协同作用，以及发现小分子 ONC201 作为一流的 TRAIL 通路诱导剂。基于新颖性 ONC201，其新兴的作用机制，我的实验室可以对现场和社会产生的具体影响对于患者而言，该提案将深入关注 ONC201 的临床前机制方向。 ONC201有作为单一疗法，已进入针对各种肿瘤类型的多项临床试验。我们的研究是提供涉及 TRAIL 的 ONC201 作用机制的重要基本信息双重阻断 ERK 和 Akt 与 Foxo3a 汇聚以激活 TRAIL 后的诱导，以及整合涉及 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，并且随着剂量的增加，我们在小鼠体内观察到抗转移作用、抑制细胞迁移以及 NK 和 T 细胞浸润到治疗中肿瘤（最近由 Wagner 等人发表，J. Clin. Invest.，2018）。我们的数据导致了变化所有开放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 细胞产生抗肿瘤和抗转移作用。目标#2：调查即时的作用 ONC201（多巴胺受体 DRD2/DRD3 亚家族）的结合靶标，介导其抗- 肿瘤作用。我们将探索假定的特定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 和整合应激通路机制由 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的状态暴露于 ONC201 的患者。我们的研究包括对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，各种细胞因子参与吸引免疫细胞到肿瘤或那些可能具有潜在免疫作用的细胞抑制，并使用 TRAIL 和 DR5 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 通过对 ONC201 试验的肿瘤标本进行分子分析来确定耐药机制评估它们在临床前模型中的作用。