ONC201 shows promise in AML treatment

KEYWORDS:

• ONC201
• leukemia
• imipridone
• TRAIL

This article refers to:

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

The 5-year overall survival rate for adults with acute myeloid leukemia (AML) treated with conventional chemotherapy is 40–45% for younger patients, while older patients have a more dismal outlook (5-year overall survival rate of 10–20%) [1]. While a high percentage of AML patients respond to induction therapy, the majority relapse. Leukemia-initiating cells (LICs), which survive cytarabine plus an anthracycline (e.g., daunorubicin)-based induction therapy, are one population thought to be responsible for relapse. Additionally, examination of leukemia stem cell frequency in paired diagnostic and relapsed AML patient samples post induction therapy revealed that at disease relapse leukemia stem cells were increased 9 to 90-fold [2]. Further complicating treatment is the inability of elderly AML patients, who make up a large portion of AML patients as the median age at diagnosis is 65–70 years, to tolerate such intensive treatment. Taken together, more effective therapies which can eliminate LICs and that are also better tolerated by the elderly are needed to treat this deadly disease.

ONC201 is a promising anti-cancer agent which is currently being evaluated in advanced clinical trials for a number of malignancies and has been shown to be well tolerated [3,4]. It was originally discovered while screening small molecules for activators of TRAIL [5]. 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 caspase-dependent 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].

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]. These encouraging results warrant further study of ONC201 in combination with cytarabine or 5-azacytidine in AML and other hematologic malignancies.

LICs likely represent mediators of residual disease and relapse post-therapy, suggesting that eradication of these cells is imperative for effective therapies. ONC201 has been shown to target LICs [7], though evidence of long-lasting effects is needed. While the combination of ONC201 shows synergistic effects against AML cells, it is of great importance and highly worthwhile to determine if ONC201 can eradicate LICs in vivo and prevent disease relapse.