Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).
ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.
Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.
“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”
Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.
Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.
The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.
The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.
Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.
And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.
Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).
“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”
The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.
A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.
“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”
