Discovery and clinical introduction of first-in-class imipridone ONC201

Joshua E. Allen, C. Leah B. Kline, Varun V. Prabhu, Jessica Wagner, Jo Ishizawa, Neel Madhukar, Avital Lev, Marie Baumeister, Lanlan Zhou, Amriti Lulla, Martin Stogniew, Lee Schalop, Cyril Benes, Howard L. Kaufman, Richard S. Pottorf, B. Rao Nallaganchu, Gary L. Olson, Fahd Al-Mulla, Madeleine Duvic, Gen Sheng WuDavid T. Dicker, Mala K. Talekar, Bora Lim, Olivier Elemento, Wolfgang Oster, Joseph Bertino, Keith Flaherty, Michael L. Wang, Gautam Borthakur, Michael Andreeff, Mark Stein, Wafik S. El-Deiry

Research output: Contribution to journalReview articlepeer-review

51 Citations (Scopus)

Abstract

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Original languageEnglish
Pages (from-to)74380-74392
Number of pages13
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • ATF4
  • DRD2
  • Integrated stress response
  • ONC201
  • TIC10

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