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

> **NIH NIH R01** · BROWN UNIVERSITY · 2022 · $86,816

## Abstract

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. 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.

## Key facts

- **NIH application ID:** 10598801
- **Project number:** 3R01CA173453-10S1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** WAFIK S. EL-DEIRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $86,816
- **Award type:** 3
- **Project period:** 2013-09-30 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598801

## Citation

> US National Institutes of Health, RePORTER application 10598801, ONC201/TIC10 Anti-tumor Effect Through Regulation of the TRAIL pathway (3R01CA173453-10S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10598801. Licensed CC0.

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