Using Genetics to Identify New Endometrial Cancer Therapeutics
Abstract
Endometrial cancer (fiscal year 2022 FY22 Peer Reviewed Cancer Research Program PRCRP Topic Area) is cancer of the uterus lining and the fourth most commonly diagnosed cancer amongst American women, with around 60,000 people expected to be diagnosed in 2022. The number of people diagnosed with endometrial cancer each year is projected to double by 2030, thus representing a major health issue. Despite rising numbers of people being diagnosed and dying of endometrial cancer, it remains underfunded compared with other cancer types. This is reflected in the lack of new endometrial cancer drugs, with only three drugs approved for use for endometrial cancer treatment in the last 50 years. It is clear that there is a need for new and innovative approaches for endometrial cancer drug discovery, especially as survival rates have not improved for decades and there is a lack of treatment options. We hypothesize that using large-scale genetic information we will find genes that cause endometrial cancer and provide opportunities for development of effective drug therapies. This approach to the identification of drug targets is supported by the recent observation that targets with genetic evidence are up to four times more likely to lead to a drug that is approved for clinical use. Our project will use state-of-the-art endometrial models called organoids (miniaturized 3D structures resembling tissue) to study the role of genetics in endometrial cancer development. These organoids, also known as organs in a dish, more accurately represent human endometrial tissue and tumors than commonly used models. Our study will be performed using organoids representing normal endometrium, a noncancerous endometrial cancer precursor and different types of endometrial tumors (including those associated with more aggressive disease). We will perform large-scale genetic experiments on these organoids to identify genetic features that affect the regulation of genes (Aim 1). We will then target genes that are at regions associated with endometrial risk and identify those that affect the development and growth of organoids (Aim 2). Lastly, the information from Aim 1 and Aim 2 will be integrated together with genetic information derived from endometrial cancer patients to identify which genes likely cause endometrial cancer and may provide effective targets for drug therapy (Aim 3). This project will study the FY22 PRCRP Overarching Challenge: Therapeutics Category, Identify and elucidate the mechanisms behind cancer epigenetics/genetics and cancer development to improve treatment methods. Through the identification of drug targets that underlie endometrial cancer genetics, the short-term impact of this research will be to set in motion the development of new treatments. The first step will be to assess the targets uncovered by our research for therapeutic opportunities from repurposing existing drugs that are already used to treat people or new drugs identified from screening large libraries of compounds. These future studies will provide lead drug candidates for clinical trials to identify effective treatments for endometrial cancer patients. Current treatment options available to endometrial cancer patients are limited, usually hysterectomy followed by additional treatment (e.g., chemotherapy or radiotherapy) for those patients with aggressive or advanced disease. Increasing the number of treatment options through the development of new drugs will significantly improve patient outcomes for those who do not respond to such additional treatments. Notably, this group of patients proportionally includes more Black patients, who are more frequently diagnosed with aggressive disease and twice more likely to die from endometrial cancer than white patients. This project addresses the FY22 PRCRP Military Health Focus Area: Gaps in cancer research that may affect mission readiness. Rates of endometrial cancer are expected to mirro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310764
Entities
People
- Tracy O Mara
Organizations
- QIMR Berghofer Medical Research Institute
- United States Army