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.

ONC201 shows promise in AML treatment

“…El-Deiry and colleagues have shown that ONC201 targets the integrated stress response and inhibits AKT and ERK, resulting in apoptosis [5]. In this report, the El-Deiry lab investigated single agent efficacy of ONC201 in a broad range of hematologic malignancies [6]. In line with previous reports [7], they found that ONC201 induces caspasedependent apoptosis in hematological malignancies.…”

“…In line with previous reports [7], they found that ONC201 induces caspasedependent apoptosis in hematological malignancies. The authors expand on their findings and show that ONC201 inhibited Akt and IAP, while downregulating anti-apoptotic proteins Bcl-2 and Bcl-xl and upregulating the pro-apoptotic protein Bim in AML cells, changes which would be expected to enhance apoptosis-inducing agents [6].…”

“…Accordingly, the authors investigated ONC201 in combination with cytarabine or 5-azacytidine in AML cells and found that both chemotherapy drugs synergize with ONC201 in AML cell lines [6]. Further, the authors show in vivo efficacy of ONC201 combined with cytarabine in a lymphoma xenograft model [6]. These encouraging results warrant further study of ONC201 in combination with cytarabine or 5-azacytidine in AML and other hematologic malignancies.…”

“…While ONC201 shows impressive single agent activity, monotherapies are vulnerable to acquired resistance. Accordingly, the authors investigated ONC201 in combination with cytarabine or 5-azacytidine in AML cells and found that both chemotherapy drugs synergize with ONC201 in AML cell lines [6]. Further, the authors show in vivo efficacy of ONC201 combined with cytarabine in a lymphoma xenograft model [6].…”

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

“…This results in dual inactivation of Akt/ERK signaling that drives Foxo3a-mediated TRAIL gene induction to promote pro-apoptotic and anti-proliferative effects in tumor cells, but not in normal cells [16][17][18][19][20] . With p53-independency, low toxicity and excellent penetration of the BBB, ONC201 is currently being evaluated in multiple clinical trials for select advanced malignancies, including myeloma, leukemia, lymphoma, endometrial cancer, high grade glioma, and other solid tumors [21][22][23][24][25][26][27][28] .…”