Aggressive Ovarian Cancer Linked to Gene Suppression, New Treatments Emerge

Researchers Identify CDK12 as Key Target in Deadly Form of Disease

A groundbreaking study has pinpointed a genetic vulnerability in high-grade serous carcinoma, the most common and often fatal type of ovarian cancer, offering a potential new avenue for treatment. The research focuses on the role of the CDK12 gene and its impact on tumor growth and immune response.

Tumor Suppressor Role Revealed

Scientists at the University of Michigan Rogel Cancer Center have demonstrated, using a novel mouse model, that CDK12 functions as a tumor suppressor in this aggressive cancer. When CDK12 is inactivated, tumors grow rapidly, and the disease becomes significantly more lethal. This is the first demonstration of in a mouse model that CDK12 plays a tumor suppressor role in this type of cancer. When we inactivate CDK12, tumors grow a lot faster and the mice die sooner, showing that this is a more aggressive form of the disease.” said Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology.

Building a Realistic Model

The success of this research hinged on the creation of a highly accurate mouse model. This model, built upon previous work by Kathleen R. Cho, M.D., involved the inactivation of four genes crucial to the development of high-grade serous carcinoma. Cho emphasized the importance of validating model systems, stating, It is very important to credential the model systems by showing they recapitulate key features of their human counterparts, a process that is also very time-consuming.”

These features include the origin of the cancer cells, microscopic appearance, timing of tumor development, genetic alterations, and even the tumor’s microenvironment.

Immune Response and Combination Therapy

Interestingly, disabling CDK12 not only accelerated tumor growth but also triggered an immune response, attracting T cells to the tumor site. Researchers then identified CDK13 as a related gene and a potential target for a degrader, a molecule designed to destroy the protein. Combining a CDK12/13 degrader with immune checkpoint inhibitors in the mouse model significantly reduced tumor growth, suggesting a promising combination therapy approach.

Ovarian cancer is a major health concern, with an estimated 22,530 new cases of ovarian cancer expected in the United States in 2024, according to the American Cancer Society (American Cancer Society, 2024). Despite advancements, survival rates remain low, particularly when the cancer becomes resistant to initial chemotherapy.

Expanding the Understanding of CDK12

This isn’t the first time Chinnaiyan’s team has linked CDK12 to aggressive cancer. Previous research demonstrated a similar role for the gene in prostate cancer, where it’s found in approximately 7% of metastatic cases. CDK12 inactivation appears less common in other cancer types, occurring in about 3% of tubo-ovarian high-grade serous cancers.

“The types of therapies that might be tried in ovarian cancer are different than prostate cancer. Here, we bring the two diseases together and show that CDK12/13 inhibitors or degraders should be considered in both these cancer types.”

—Arul M. Chinnaiyan, M.D., Ph.D.

Several CDK12/13 inhibitors are currently in development, including a compound created by the U-M team. The researchers are now focused on refining the CDK12/13 degrader with the ultimate goal of initiating a clinical trial.

Note: This research is preclinical, and a CDK12/13 degrader is not yet available for clinical trials. For information on current clinical trials or questions about ovarian cancer treatment, call the Michigan Medicine Cancer AnswerLine at 800-865-1125 or visit www.rogelcancercenter.org/clinical-trials.