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 i nclude:
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.

Public Health Relevance

This research program is directed towards the highly significant problem of drug resistance in advanced cancer that may be addressed by targeting anti-tumor cell death signaling pathways. The proposal builds on discovery in the El-Deiry Lab of a new drug ONC201 targeting the TRAIL death receptor pathway that has been brought into multiple clinical trials and is showing promising activity in multiple tumor types including prostate cancer, GBM, uterine cancer, lymphoma, leukemia and colorectal cancer. The proposal provides unique and novel mechanistic insights regarding signaling within tumor cells including immune stimulation by ONC201, involvement of dopamine receptors, and explores drug resistance mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA173453-08
Application #
9924502
Study Section
Mechanisms of Cancer Therapeutics - 1 Study Section (MCT1)
Program Officer
Kondapaka, Sudhir B
Project Start
2013-09-30
Project End
2024-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Brown University
Department
Pathology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Wagner, Jessica; Kline, C Leah; Zhou, Lanlan et al. (2018) Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms. J Exp Clin Cancer Res 37:11
Lev, Avital; Lulla, Amriti R; Ross, Brian C et al. (2018) ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer. Mol Cancer Res 16:754-766
Wagner, Jessica; Kline, C Leah; Zhou, Lanlan et al. (2018) Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. J Clin Invest 128:2325-2338
Kline, Christina Leah B; Ralff, Marie D; Lulla, Amriti R et al. (2018) Role of Dopamine Receptors in the Anticancer Activity of ONC201. Neoplasia 20:80-91
Ralff, Marie D; Kline, Christina L B; Küçükkase, Ozan C et al. (2017) ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms. Mol Cancer Ther 16:1290-1298
Ralff, Marie D; Lulla, Amriti R; Wagner, Jessica et al. (2017) ONC201: a new treatment option being tested clinically for recurrent glioblastoma. Transl Cancer Res 6:S1239-S1243
Lev, Avital; Lulla, Amriti R; Wagner, Jessica et al. (2017) Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. Oncotarget 8:81776-81793
El-Deiry, Wafik S (2016) p21(WAF1) Mediates Cell-Cycle Inhibition, Relevant to Cancer Suppression and Therapy. Cancer Res 76:5189-91
Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V et al. (2016) Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget 7:74380-74392
Kline, C Leah B; Van den Heuvel, A Pieter J; Allen, Joshua E et al. (2016) ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2? kinases. Sci Signal 9:ra18

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