First-in-Class Drug Shows Promise in Leukemia, Lymphoma

ONC201 caused p53-independent cell death and cell cycle arrest in lymphoma and acute leukemia patient samples.

A recent clinical trial showed the potential of an anti-cancer drug to treat blood cancers that include mantel cell lymphoma (MCL) and acute myeloid leukemia (AML).

Researchers at the University of Texas MD Anderson Cancer Center found in early clinical trials that the first-in-class drug ONC201 was able to cause cell death even when the p53 protein was mutated or deleted entirely.

This dysfunction is found to occur in more than half of malignancies and can promote tumor resistance to chemotherapy.

"The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required," said lead researcher Michael Andreeff, MD, PhD. "We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples."

The study, published in Science Signaling, used samples of patients with genetic abnormalities associated with poor prognosis or who had developed a resistance to anti-cancer drugs ibrutinib and bortezomib.

Furthermore, mouse models found that ONC201 caused cell death in leukemia and AML stem cells, but did not harm normal bone marrow cells.

The results of the study showed that ONC201 increased the translation of stress-induced protein ATF4 through stress signals. These are similar to those caused by cellular responses: unfolded protein response (UPR) and integrated stress response.

In order for cellular proteins to survive, they must be properly folded. UPR is the major response against unfolded proteins. Prolonged or excess UPR can eventually lead to cell death.

Deprivation of nutrients and viral infections can cause ISR. ATF4 is commonly induced in these responses by ONCO201 treatment. ATF4 has the ability to turn specific genetic instructions on and off.

"This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death," Andreeff said. "However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells promoted was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cell to death regardless of p53 status. There is clear evidence that ONC201 has clinical potential in hematological malignancies. Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson."