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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：
10452763
负责人：
WAFIK S. EL-DEIRY
金额：
$ 47.44万
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/10452763
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 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 Tumor-infiltrating immune cells Uterine Cancer analog antagonist 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.

项目总结