Targeting the SRPK1-AKT Signaling Axis in Endometrial Cancer
Abstract
Endometrial carcinoma (EC), a cancer of the endometrium (the lining of the uterus), is the most common gynecologic malignancy in the United States, with 65,950 new cases and 12, 550 deaths expected in 2022. Strikingly, there has been an approximate 25 % increase in deaths due to endometrial cancer over the last 6 years (10,470 deaths in 2016), highlighting the importance of studying this deadly disease. Uterine serous carcinoma (USC), is the deadliest form of EC that accounts for approximately 80% of all EC-associated deaths. The current treatment for advanced USC includes debulking surgery and paclitaxel/platinum-based chemotherapies. Despite high initial response, the majority of patients relapse within 3 years, for which there are no follow-up treatments. The high mortality rate of USC patients is due to frequent drug resistance and metastasis, which is the spreading of cancer cells from the primary tumor site to other regions of the body. Thus, there is an urgent need to identify new drug targets and to develop new drug treatments that can be rapidly translated into clinical trials for the treatment of USC. Targeted therapies are cancer treatments that use drugs to selectively block the function of one or more cancer genes and are often associated with personalized medicine. One of the most promising classes of targeted therapies are protein kinase inhibitors – drugs that block the function of a specific class of enzymes that help cancers cells grow, survive, and metastasize. These kinases are highly amenable to drug development, making the design and translation of kinase inhibitors for cancer therapies clearly attainable. Protein kinase inhibitors have shown dramatic therapeutic responses in cancer patients, causing complete regression of tumors that were previously untreatable, including cancers that have spread throughout the body. There are over 500 protein kinases in cancer cells, and many of these kinases have already been shown to be effective anticancer targets. Importantly, more than 60 kinase inhibitors are currently U.S. Food and Drug Administration-approved for the treatment of cancer, with several hundred in clinical trials for a variety of cancers. Our laboratory has expertise in the study of protein kinases in cancer and possesses unique technologies that allow us to identify new kinase targets for the treatment of cancer. Using these technologies, our lab recently discovered a new kinase target for USC called SRPK1, which we believe represents a very promising new drug target for the treatment of USC. Following a detailed characterization of this kinase in endometrial cancer cell models, we discovered it was important for many key cancer-related processes, and if we blocked its function using kinase inhibitors, we could prevent cancer growth and survival. Importantly, in preliminary in vivo studies using USC mouse models, we showed treatment of mice with drugs targeting SRPK1 was safe, tolerable, and had tumor inhibiting properties, highlighting SRPK1 as a promising new therapeutic avenue for USC. Additionally, our lab discovered that combining SRPK1 inhibitors with another kinase inhibitor that targets the protein kinase AKT, improved growth repression and killing of EC cells. Notably, AKT is overactivated in the majority of EC; however, a recent clinical trial evaluating AKT inhibitors in USC patients showed blocking AKT function in tumors had minimal clinical benefit in USC patients. Importantly, our preliminary findings suggest that the addition of SRPK1 inhibitors could improve the antitumor responses elicited by AKT inhibitors for the treatment of USC patients, which could be rapidly translated into clinical trials. Based on our preliminary studies detailed above, we hypothesize SRPK1 represents a promising drug candidate in combination with AKT inhibitors for the treatment of USC that could have dual tumor inhibiting and anti metastatic benefits for EC patients. In the propo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310751
Entities
People
- James S Duncan
Organizations
- United States Army