Defensive Maneuver

Sahin, I., Zhang, S., Navaraj, A., Zhou, L., Dizon, D., Safran, H., & El-Deiry, W. S. (2020). AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing. Cell Death Discovery, 6(1), 57. doi:10.1038/s41420-020-0292-1

Immunotherapy fails in a significant proportion of cancer patients. But a new study in Cell Death Discovery suggests that blocking the tumor-promoting protein MDM2 could bolster the treatment’s effectiveness.

“Immunotherapy has been one of the biggest breakthroughs in biomedical science and medicine of the last two decades,” says Wafik S. El-Deiry, MD, PhD, a professor of pathology and laboratory medicine and associate dean for oncologic sciences. “But it has limitations.”

Some people’s tumors respond to immunotherapy initially and then relapse. Other patients experience pseudoprogression, where tumors appear to grow before eventually shrinking. And a third group—between 5 percent and 29 percent of patients—experience hyperprogression: immunotherapy actually worsens their tumor growth.

El-Deiry hopes that blocking MDM2, either through gene silencing or the MDM2-inhibiting drug AMG-232, could help people with hyperprogression.

Various studies have found that when cells contain too many copies of the MDM2 gene, or when the MDM2 protein is overexpressed because the gene isn’t being regulated properly, tumor cells tend to grow more quickly and are more resistant to immunotherapy. MDM2 is also associated with higher levels of the tumor-promoting inflammatory protein interleukin-6 (IL-6).

In their study, El-Deiry and his colleagues treated cell lines of MDM2-overexpressing ovarian cancer cells with AMG-232. Their data show the drug allowed immune cells to kill the tumor cells much more efficiently, and reduced levels of IL-6. This suggests that MDM2 inhibitors combined with immunotherapy could enhance its effectiveness, and El-Deiry hopes this will lead to a clinical trial.

The study was published shortly after the launch of the Cancer Center at Brown, which brings together 150 investigators from across the University and affiliated hospitals who are studying basic biology and disease epidemiology, understanding risk factors, and developing therapies.

The center focuses on cancers with higher rates in Rhode Island, as well as issues of access and affordability. El-Deiry, the center’s inaugural director, wants the center to achieve a National Cancer Institute-Cancer Center Support Grant.

“We are working methodically, in a focused way, toward that,” he says, “collaborating for the benefit of patients.”