Converting Mutant p53 into an Actionable Target for the Treatment of Ovarian Cancer
Abstract
Ovarian cancer remains one of the most deadly diseases in women. The current care of women with ovarian cancer is limited by our inability to personalize therapy, meaning we treat all women with ovarian cancer in just about the same way: surgery followed by chemotherapy (carboplatin + paclitaxel) for six months. Our progress over the years in increasing survivorship has been minimal. Today, 70% of women die of their disease. Given that we are in the molecular age, our thesis is that physicians should take advantage of the “Achilles’ heel” of every tumor. That means we should understand the survival pathways unique to each patient’s tumor and target them using rationally designed treatments. Our team’s work focuses on a gene, TP53, which is mutated in 95% of all ovarian cancers. We have also studied how each mutation in this gene affects the survival mechanisms of cancer cells, and we believe we have identified highly effective ways to block those survival pathways. The end result is that tumor cells die. In this grant, we extend our previous studies to better understand all of the different varieties of TP53 mutations that occur in ovarian cancer. For example, some mutations cause the protein encoded by TP53 to lose expression, whereas other mutations endow the protein with new and detrimental properties that allow cancer to be resistant to chemotherapy. This grant provides proof of principle that new and more effective treatments can become a reality for women with ovarian cancer by targeting these survival pathways that arise specifically in response to mutations in this most important gene. First, we will take advantage of clinical and tumor-specific data from patients enrolled on a major national clinical trial, GOG/NRG-218. To date, this is one of the largest treatment trials in ovarian cancer, and over 1,000 patients were enrolled. We are partnering with the investigators of this trial to reanalyze the data with the hypothesis that certain mutations in TP53 predict for better response to therapy that includes bevacizumab, as our data to date suggest. Building upon these insights, we will next study the impact of many types of mutations in this gene using well validated model cells and organisms. Finally, we will test new treatments aimed specifically at killing cells with different mutations in TP53. Because so many ovarian tumors have mutations in this gene, our studies will apply to most of the patients with ovarian cancer, leading to a major breakthrough in clinical management. Importantly, we are able to repurpose known drugs in novel combinations. This means that we can use agents that are already approved and have validated safety in patients with other cancer types, effectively shortening the time from bench discovery to bedside treatment of ovarian cancer patients. Ovarian cancer is a disease that affects many women around the world, including active military personnel, Veterans, and their family members. Why is ovarian cancer of particular concern for women in the military? Though little information is available on the rate of ovarian cancer in Veterans or active military personnel, one study showed that approximately 8% of women Veterans from the Vietnam War have been diagnosed with a gynecologic cancer. In addition, the spouses of male Veterans and active duty military personnel are also at risk for the development of these tumors, and ovarian cancer in particular is a disease that has been associated with environmental stress. As ovarian cancer is by far the most deadly gynecologic tumor, these studies have the potential to save lives and positively impact military families as well as the general U.S. population. Our study will provide an essential link between the most common genetic cause of ovarian cancer and new treatments that are personalized and improve the overall health and well-being of women with ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010313
Entities
People
- Kimberly K Leslie
Organizations
- United States Army
- University of Iowa