Image courtesy of PNAS
Researchers say they have determined how the investigational drug ONC201 is active against a range of malignancies.
The team found that ONC201 induced apoptosis and cell cycle arrest in multiple myeloma (MM) and solid tumor cell lines.
The drug triggered an increase in the anticancer protein TRAIL and induced cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5.
The researchers reported these findings in Science Signaling. Some researchers involved in this study are affiliated with Oncoceutics Inc., the company developing ONC201.
“We have revealed, in unprecedented detail, exactly how ONC201 works across a broad range of tumor types, and this has important clinical implications,” said study author Wafik El-Deiry, MD, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.
“For example, our findings suggest that patients with various solid tumors, as well as multiple myeloma, may be particularly sensitive to the effects of ONC201. We have identified a potential biomarker that could be used to select which patients are most likely to benefit therapeutically from this drug.”
Dr El-Deiry noted that TRAIL has been shown to induce cell death in a range of cancers while sparing normal cells. However, the therapeutic benefit of stimulating TRAIL is limited because of undesirable drug properties, such as a short half-life, difficult and expensive production, the need to give treatment as an intravenous infusion, and poor penetration into certain tissues like the brain.
“This prompted us to look for better options for therapeutics that can kill tumor cells,” Dr El-Deiry said.
He and his colleagues turned to ONC201, which has been shown to stimulate TRAIL. They tested the drug in 23 cancer cell lines representing 9 tumor types—MM, lymphoma, and glioma, as well as lung, colorectal, thyroid, liver, prostate, and breast cancer.
The team found that ONC201 triggers an increase in TRAIL and TRAIL receptor abundance, leading to tumor cell death through the ISR that tumor cells normally use to survive. ONC201 pushes the ISR too far, causing tumor cells to stop dividing and/or die.
ONC201 boosted expression of the gene encoding ATF4, a central component of the ISR, through a translation initiation factor called eIF2α. This process rapidly arrested the cancer’s cell cycle and resulted in cell death.
In essence, ONC201 delivers a double-whammy to tumor cells, Dr El-Deiry said, which may explain why it has such broad-spectrum anticancer activity.
The researchers believe this study has several clinical implications. For one, it suggests that solid tumors or MM cells that normally create large amounts of protein during growth may be particularly sensitive to ONC201. The ISR is often activated in these cells, and ONC201 may push them over the edge.
“Knowing how ONC201 works helps us look for its effects in patient’s tumor cells that have been treated,” Dr El-Deiry said. “Looking in a tumor or liquid biopsy before and after treatment may help predict who is most likely to benefit.”
“We are optimistic that, through basic and clinical research with ONC201, our findings will lead to improved TRAIL-based therapies for individual cancer patients in the future.”
Another study of ONC201, this one focusing only on hematologic malignancies, has been published in Science Signaling.
Early stage clinical trials for ONC201 are currently underway in patients with brain, colorectal, breast, and lung tumors, as well as leukemia and lymphoma.
