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: 10738317
• 负责人: WAFIK S. EL-DEIRY
• 金额: $ 9.32万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738317
• 关键词: Address; Advanced Malignant Neoplasm; American; Antitumor Response; Apoptotic; Binding; CXCL10 gene; Cell Death; Cell Death Signaling Process; Cell Migration Inhibition function; 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 D2 Receptor; Dopamine Receptor; Dose; Drug Synergism; Drug resistance; EIF-2alpha; Epigenetic Process; Exposure to; Fibroblasts; Fox Chase Cancer Center; Goals; Growth; Immune; Immune response; Immunologic Stimulation; Immunotherapy; Infiltration; Investments; Knock-out; Knockout Mice; Lymphoma; 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; 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; antagonist; anti-PD1 therapy; antitumor effect; biological adaptation to stress; cancer prevention; cancer stem cell; cancer therapy; cell type; combinatorial; cytokine; cytotoxic; first-in-human; host neoplasm interaction; human study; immune cell infiltrate; in vivo; insight; leukemia; neoplastic cell; novel; novel strategies; novel therapeutics; patient response; pharmacologic; 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DR 5和癌症的耐药机制，确定了药物协同作用， 发现了小分子ONC 201作为一流的TRAIL通路诱导剂。基于新奇 ONC 201，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ONC 201临床前机制方向。ONC 201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ONC 201作用机制的重要基础信息 在双重阻断ERK和Akt会聚在Foxo 3a上以激活TRAIL后的诱导，以及整合的 涉及eIF 2-α依赖性ATF 4/CHOP介导的TRAIL死亡诱导的应激反应 受体5。ONC 201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ONC 201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ONC 201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ONC 201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ONC 201的患者。我们的研究包括深入的免疫机制分析， ONC 201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DR 5敲除以及具有GFP（+）NK细胞的NCR 1-GFP小鼠， 分析ONC 201（或ONC 201类似物）处理的肿瘤的宿主肿瘤相互作用。我们探索ONC 201 通过来自ONC 201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。

项目成果

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.

ONC201和丙烯酮：具有临床功效的抗癌化合物。

• DOI: 10.1016/j.neo.2020.09.005
• 发表时间: 2020-12
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Prabhu VV;Morrow S;Rahman Kawakibi A;Zhou L;Ralff M;Ray J;Jhaveri A;Ferrarini I;Lee Y;Parker C;Zhang Y;Borsuk R;Chang WI;Honeyman JN;Tavora F;Carneiro B;Raufi A;Huntington K;Carlsen L;Louie A;Safran H;Seyhan AA;Tarapore RS;Schalop L;Stogniew M;Allen JE;Oster W;El-Deiry WS
• 通讯作者: El-Deiry WS

Role of Dopamine Receptors in the Anticancer Activity of ONC201.

• DOI: 10.1016/j.neo.2017.10.002
• 发表时间: 2018-01
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Kline CLB;Ralff MD;Lulla AR;Wagner JM;Abbosh PH;Dicker DT;Allen JE;El-Deiry WS
• 通讯作者: El-Deiry WS

Potent preclinical sensitivity to imipridone-based combination therapies in oncohistone H3K27M-mutant diffuse intrinsic pontine glioma is associated with induction of the integrated stress response, TRAIL death receptor DR5, reduced ClpX and apoptosis.

癌组蛋白 H3K27M 突变型弥漫性内源性脑桥神经胶质瘤对基于亚咪啶酮的联合疗法的有效临床前敏感性与综合应激反应、TRAIL 死亡受体 DR5、ClpX 减少和细胞凋亡的诱导有关。

• 发表时间: 2021
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Borsuk,Robyn;Zhou,Lanlan;Chang,Wen-I;Zhang,Yiqun;Sharma,Aditi;Prabhu,VarunV;Tapinos,Nikos;Lulla,RishiR;El-Deiry,WafikS
• 通讯作者: El-Deiry,WafikS

Novel combination of imipridones and histone deacetylase inhibitors demonstrate cytotoxic effect through integrated stress response in pediatric solid tumors.

亚咪啶酮和组蛋白脱乙酰酶抑制剂的新型组合通过儿童实体瘤的综合应激反应证明了细胞毒性作用。

• 发表时间: 2023
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Chang,Wen-I;Honeyman,JoshuaN;Zhang,Jun;Lin,Claire;Sharma,Aditi;Zhou,Lanlan;Oliveira,Janice;Tapinos,Nikos;Lulla,RishiR;Prabhu,VarunV;El-Deiry,WafikS
• 通讯作者: El-Deiry,WafikS

Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors.

• DOI: 10.1371/journal.pone.0180541
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Prabhu VV;Lulla AR;Madhukar NS;Ralff MD;Zhao D;Kline CLB;Van den Heuvel APJ;Lev A;Garnett MJ;McDermott U;Benes CH;Batchelor TT;Chi AS;Elemento O;Allen JE;El-Deiry WS
• 通讯作者: El-Deiry WS