Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in
Varun V Prabhu1, Mala K Talekar2, Amriti R Lulla3
1a Oncoceutics, Inc. , Philadelphia , PA.
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.
Insights
ONC201 shows efficacy against various blood cancers, including leukemia and lymphoma, by inducing cancer cell death. It also enhances the effectiveness of standard treatments, supporting its use in clinical trials.
Area of Science:
- Oncology
- Hematology
- Molecular Biology
Background:
- ONC201 is an imipridone molecule in advanced cancer clinical trials.
- Hematological malignancies represent a significant area of unmet medical need.
- Preclinical models are crucial for evaluating novel therapeutic agents.
Purpose of the Study:
- To assess the single-agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies.
- To identify potential biomarkers for ONC201 activity.
- To establish a rationale for clinical trials of ONC201.
Main Methods:
- Evaluated ONC201 efficacy in a panel of hematological cancer cell lines and primary samples.
- Investigated the molecular mechanisms of ONC201-induced cell death, including apoptosis and stress response pathways.
- Assessed synergistic effects of ONC201 in combination with standard chemotherapeutic agents in vitro and in vivo.
Main Results:
- ONC201 demonstrated dose- and time-dependent efficacy across various leukemia, lymphoma, and multiple myeloma cell lines, including drug-resistant cells.
- ONC201 induced caspase-dependent apoptosis via integrated stress response (ATF4/CHOP) pathway activation.
- ONC201 showed synergistic activity with cytarabine, 5-azacytidine, bortezomib, ixazomib, and dexamethasone in preclinical models.
Conclusions:
- ONC201 exhibits broad preclinical efficacy in hematological malignancies.
- ONC201's mechanism involves apoptosis induction and integrated stress response activation.
- These findings support ONC201 as a single agent or in combination therapy for hematological cancers.
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