Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies.

Abstract

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

• Authors: Varun V Prabhu, Mala K Talekar, Amriti R Lulla, C Leah B Kline, Lanlan Zhou, Junior Hall, A Pieter J Van den Heuvel, David T Dicker, Jawad Babar, Stephan A Grupp, Mathew J Garnett, Ultan McDermott, Cyril H Benes, Jeffrey J Pu, David F Claxton, Nadia Khan, Wolfgang Oster, Joshua E Allen, Wafik S El-Deiry
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 17 Issue 4 Pg. 468-478 ( 2018) ISSN: 1551-4005 [Electronic] United States
• PMID: 29157092 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATF4 protein, human
• Antineoplastic Agents
• Boron Compounds
• DDIT3 protein, human
• Heterocyclic Compounds, 4 or More Rings
• Imidazoles
• Pyridines
• Pyrimidines
• Activating Transcription Factor 4
• Transcription Factor CHOP
• ixazomib
• TIC10 compound
• Azacitidine
• Glycine

Topics

• Activating Transcription Factor 4 (metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Azacitidine (pharmacology)
• Boron Compounds (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Drug Synergism
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Glycine (analogs & derivatives, pharmacology)
• Hematologic Neoplasms (drug therapy, metabolism, pathology)
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Humans
• Imidazoles
• Mice
• Mice, SCID
• Pyridines
• Pyrimidines
• Transcription Factor CHOP (metabolism)
• Transplantation, Heterologous