In a new study, researchers at the University of Texas MD Anderson Cancer Center found that ONC201, a first-in-class anticancer drug being developed in partnership with Oncoceutics Inc., caused cancer cell death in cell lines and in patients’ samples with mantle cell lymphoma (MCL) and acute myeloid leukemia (AML). The death of cancer cells takes place through a molecular pathway independent of p53, whose abnormalities pose serious clinical problems in anti-cancer therapy.
The research paper, “ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies,” was published in Science Signaling.
ONC201, currently in early clinical trials, is a promising anticancer drug due to its ability to kill cancer cells without causing harmful effects on healthy cells. The drug’s clinical relevancy is supported by the fact that it induces P53-independent apoptosis (programmed cell death). The tumor suppressor protein p53 is mutated or deleted in a great proportion of blood cancers. This dysfunction is associated with poor prognosis malignant characteristics, such as metastasis and resistance to chemotherapy treatment, so finding alternative therapies to standard chemotherapy is of urgent.
The patients’ samples included in the study included those of cancers with genetic abnormalities linked to poor prognosis or that had demonstrated resistance to drugs commonly used for lymphoma, such as ibrutinib and bortezomib. In these cell lines and samples, the drug caused cell death through a p53-independent pathway.
Also, mouse studies revealed that ONC201 caused cell death in AML and leukemia stem cells, while normal bone marrow cells remained unharmed. Researchers described the molecular mechanisms involved in the ONC201 effect. The drug caused changes in genetic expression that are also observed in the cellular events of UPR (unfolded protein response) and ISR (integrated stress response), the cell’s response to improper protein folding (UPR), nutrient deprivation and viral infection (ISR), ultimately resulting in cell death. Both responses, and ONC201 treatment, induce higher levels of the transcription factor ATF4.
“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” said study leader Michael Andreeff, MD. “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.”