A promising genetic clue could lead to improvements in the effectiveness of cancer treatments in certain patients, according to a study recently published in Nature.
Ovarian clear cell carcinoma (OCCC) is a rare and aggressive form of ovarian cancer that is notoriously hard to treat. Traditional chemotherapy is often ineffective, and alternatives such as targeted therapy or immunotherapy only work for some patients, said Emily Hinchcliff, MD, MPH, assistant professor of Obstetrics and Gynecology in the Division of Gynecologic Oncology, who was a co-author of the study.
“While immunotherapy has been this incredible game-changer in how we think about cancer treatment, unfortunately, in ovarian cancer, the impact of immunotherapy has thus far been limited with relatively low response rates,” said Hinchcliff, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
In the current study, Hinchcliff and her collaborators investigated outcomes in a cohort of 34 patients with treatment-resistant ovarian clear cell cancer (OCCC) who had been treated with a form of immunotherapy called immune checkpoint blockade, which enhances the immune system’s ability to recognize and destroy cancer cells. They found that patients with PPP2R1A-mutant OCCC had a median overall survival (OS) of more than five years (66.9 months) after immunotherapy treatment, compared to just 9.2 months for patients without this mutation.
Next, investigators also checked two additional cohorts of patients, including a dataset of over 9,000 patients who had received immunotherapy treatment. Across multiple cancer types, PPP2R1A mutations were linked to better outcomes, according to the study.
“However, it’s important to note that PPP2R1A does not seem to be a prognostic marker independently; It’s only in those patients that are treated with immune checkpoint inhibitors where it serves as a biomarker with a statistically significant improvement in overall survival,” Hinchcliff said.
In vitro and in vivo models then demonstrated that targeting PPP2R1A resulted in a stronger immune response signaling and an increase in CD8+ T cells—immune cells that “remember” threats and respond quickly. This suggests a causal link between the genetic mutation and improved response to immunotherapy.
Building off this discovery, Hinchliff and her collaborators have already begun a clinical trial aimed at targeting PPP2R1A and the associated molecular pathway in combination with immune checkpoint inhibition.
“In the current published study, only patients whose tumors have inherent mutations in PPP2R1A were included, which makes up only about 10 percent of ovarian clear cell carcinoma, already a rare cancer,” Hinchcliff said. “Therefore, we’ve now started a clinical trial using a pharmacologic inhibitor to try and target the same pathway for those without the mutation, to determine if the same benefits may be possible in combination with immunotherapy. This trial is only open at MD Anderson Cancer Center and here at Northwestern. It’s a really unique opportunity for patients with this rare and aggressive cancer.”
The study was supported by the National Institutes of Health T32 training grant, Dunwoody-Edwards-Reese philanthropic support, and grants from the National Institutes of Health, Department of Defense, and the American Cancer Society.
