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

Autor: Amriti R. Lulla, Jeffrey J. Pu, Jawad Babar, Nadia Khan, Cyril H. Benes, Lanlan Zhou, Joshua E. Allen, A. Pieter J. van den Heuvel, Ultan McDermott, Mala K. Talekar, Mathew J. Garnett, C. Leah B. Kline, Junior Hall, Wolfgang Oster, David F. Claxton, Varun V. Prabhu, David T. Dicker, Wafik S. El-Deiry, Stephan A. Grupp
Rok vydání: 2018
Předmět:
Boron Compounds
0301 basic medicine
Cell Survival
Pyridines
Chronic lymphocytic leukemia
Transplantation
Heterologous
Glycine
Antineoplastic Agents
Apoptosis
Mice
SCID
CHOP
Pharmacology
Biology
Heterocyclic Compounds
4 or More Rings
Mice
03 medical and health sciences
0302 clinical medicine
immune system diseases
Cell Line
Tumor
hemic and lymphatic diseases
medicine
Animals
Humans
Molecular Biology
Anaplastic large-cell lymphoma
Acute leukemia
Bortezomib
Imidazoles
Drug Synergism
Cell Biology
medicine.disease
Activating Transcription Factor 4
G1 Phase Cell Cycle Checkpoints
Lymphoma
Pyrimidines
Cell Cycle News and Views
030104 developmental biology
Hematologic Neoplasms
030220 oncology & carcinogenesis
Azacitidine
Cytarabine
Cancer research
Mantle cell lymphoma
Drug Screening Assays
Antitumor
Transcription Factor CHOP
Reports
Developmental Biology
medicine.drug
Zdroj: Cell Cycle. 17:468-478
ISSN: 1551-4005
1538-4101
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: