The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

Wagner, Jessica; Kline, Christina Leah B.; Pottorf, Richard S.; Nallaganchu, Bhaskara Rao; Olson, Gary L.; Dicker, David T.; Allen, Joshua E.; El‐Deiry, Wafik S.

doi:10.18632/oncotarget.2890

Cited by 42 publications

(38 citation statements)

References 8 publications

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“…Since surface TRAIL protein is cleaved to form a soluble ligand, assaying serum levels in addition to tumor cell expression of TRAIL is suggested for pharmacodynamic studies in ongoing clinical trials of ONC201. ONC201 is a first-in-class compound with a unique pharmacophore 33 and associated novel mechanism of action. The mechanism of ONC201 remains an area of active study, particularly the upstream signaling mechanisms that trigger its late anti-cancer effects that appear to involve both cytostatic and cytotoxic phenotypes in a cell-type dependent manner.…”

Section: Discussionmentioning

confidence: 99%

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

Talekar¹,

Allen

Dicker

et al. 2015

Cell Cycle

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Abbreviations: TRAIL, TNF-related apoptosis-inducing ligand; DR5, death receptor 5; TNF, tumor necrosis family; NHL, non-Hodgkin's lymphoma.ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.

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Section: Discussionmentioning

confidence: 99%

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

Talekar¹,

Allen

Dicker

et al. 2015

Cell Cycle

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“…ONC201 is the first member of the imipridone class of small molecules (12,13). The compound is currently being tested in phase II clinical trials of patients with hematological malignancies and solid tumors (14,15).…”

Section: Preclinical Activity Of Onc201 In Glioblastomamentioning

confidence: 99%

ONC201: a new treatment option being tested clinically for recurrent glioblastoma

et al. 2017

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Glioblastoma is an aggressive central nervous system tumor with a 5-year-survival rate of less than 10%. Patients diagnosed with the disease are treated with surgery, radiation and temozolomide chemotherapy. Despite survival benefits, patients eventually relapse. There is a need for new treatments with improved efficacy. Imipridone ONC201 is a small molecule originally identified as a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound. ONC201 has the unique ability to induce expression of both pro-death ligand TRAIL and its receptor DR5 through engagement of the cellular integrated stress response (ISR) pathway. Arrillaga-Romany et al. report early results from futility analysis of a phase II clinical trial of ONC201 in 17 patients with recurrent or refractory glioblastoma conducted at the Massachusetts General Hospital Cancer Center. The results are promising, as ONC201 shows preliminary signs of efficacy. Further testing of ONC201 in an expansion cohort of patients with glioblastoma is ongoing.

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“…We also recently demonstrated potent antitumor effects on colorectal cancers initiated by cancer stem/progenitor cells (CSCs) (7). In vivo, first-in-class small molecule ONC201 exhibits a broad spectrum of anticancer activity, a wide safety margin, robust stability, aqueous solubility, blood-brain barrier penetration, and favorable pharmacokinetics (1)(2)(3)(4)(5)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment

Wagner¹,

Kline²,

Zhou³

et al. 2018

Journal of Clinical Investigation

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ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.

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The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

Cited by 42 publications

References 8 publications

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

ONC201: a new treatment option being tested clinically for recurrent glioblastoma

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment

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