New $15 million grant to Dana-Farber scientists supports research into innovative approaches to endometrial cancer treatment

Physician-scientists at Dana-Farber Cancer Institute have received a five-year, $15 million Program Project Grant from the National Cancer Institute (NCI) for research in endometrial cancer, which arises in the inner lining of the uterus and strikes more than 68,000 women a year in the U.S. It is one of only two forms of cancer in which survival rates have not significantly improved since the mid-1970s.

The grant will fund three research projects focusing on a key characteristic of many endometrial cancers, especially those that are high grade and have an aggressive nature. This unique feature, known as replication stress, slows or stops the process of DNA duplication in the cell cycle, creating the genomic instability that is a hallmark of cancer. Each of the projects will explore a different approach to targeting replication stress as a vulnerability in endometrial cancer cells.

Program Project or P01 grants from the NCI support a set of cancer research projects that are directed at a specific objective. The projects involve multiple independent investigators who pool their knowledge and share resources.

"The incidence of endometrial cancer in the United States is rising at an overall rate of 1% a year, and is increasing even faster among non-white populations," says Ursula Matulonis, MD, Chief of the Division of Gynecologic Oncology at Dana-Farber and co-principal investigator of the program with Dana-Farber's Panagiotis Konstantinopoulos, MD, PhD, director of translational research, Gynecologic Oncology, and Joyce Liu, MD, MPH, associate chief and director of clinical research, Gynecologic Oncology. "At the same time, there are racial and ethnic disparities in both incidence and survival for this disease, with Black women at higher risk to develop the disease, and more likely to die of it, than white women. These trends make it urgent that we develop new treatment strategies, particularly for patients with advanced or relapsed cancer."

The three projects funded by the grant are:

• Research into the molecular mechanism by which targeted drugs known as WEE1 inhibitors are active in recurrent uterine serous cancer, an uncommon but aggressive subtype of endometrial cancer, and in uterine cancer harboring a mutation in the p53 gene. The project builds on a clinical trial led by Liu and Konstantinopoulos that found the WEE1 inhibitor adavosertib had significant activity in these cancers. As part of the project, investigators will study ways of measuring replication stress and will explore whether such measurements can be biomarkers of whether certain medications are showing effectiveness against the disease.
• Research into the hypothesis that inhibiting the PI3K protein pathway with a drug agent can increase replication stress in endometrial tumor cells and therefore work synergistically with targeted drugs known as ATR inhibitors. Previous research has suggested these two approaches can reinforce each other.
• Research into the possibility of targeting two types of "checkpoint" proteins in endometrial cancer cells. One acts as a checkpoint on repair of DNA damage. The other acts as a checkpoint on the immune response to cancer. Previous studies showed that inhibiting certain DNA damage checkpoint proteins resulted in increased DNA damage and a more powerful immune attack on endometrial tumor cells. Researchers reasoned that combining inhibitors of DNA damage checkpoint proteins with immune checkpoint proteins could be a promising approach to targeting replication stress.

"Each of these projects has great potential for improving the treatment of endometrial cancer by targeting replication stress," Matulonis remarks. "The insights that these projects will generate into the vulnerabilities created by replication stress will be critical to the development of better therapies for patients with relapsed or advanced forms of endometrial cancer, especially those with high-grade types such as serous and carcinosarcoma histologies."

Additional project leaders associated with the grant include Dipanjan Chowdhury, PhD, and Jean Zhao, PhD, both of Dana-Farber.