Women's Health Research at Yale’s first Wendy U. and Thomas C. Naratil Pioneer Award was granted earlier this year to Dr. Alfred Bothwell for a study targeting the development of optimized treatments for uterine serous cancer that can be tailored to individual patients with this very aggressive form of endometrial cancer.
With approximately 50,000 new cases and more than 8,000 deaths annually, endometrial cancer is the most common gynecological cancer among American women. Uterine serous cancer accounts for only 10 percent of endometrial cancer cases, but is responsible for nearly 40 percent of endometrial cancer deaths. Clearly, improved treatment strategies are urgently needed.
Bothwell, Professor of Immunobiology, has focused his research in part on how key immune cells function and the development of immunotherapies (treatments that use the body’s own immune system to fight cancer) to optimize cancer therapies. In this inaugural Naratil Pioneer Award study, he is beginning to tackle the desperate need for a new way to combat uterine serous cancer.
His approach is to develop a radically innovative mouse model of uterine serous cancer that will more closely simulate a patient’s experience, by integrating the patient’s immune system and tumor pathology.
Current models typically employed to test anti-cancer agents do not consistently predict patient outcomes. Bothwell and other scientists working in this area believe this is because the models do not account for how the immune system influences both tumor growth and response to a given therapy.
“We want to make a model in which you have the tumor and the immune system of the same patient,” Bothwell said. Using this new model, tests will be conducted to identify which immunotherapies and other medications or combinations used to treat uterine serous cancer will work for individual patients. He expects this new model to usher in “personalized medicine” for this type of cancer and potentially other types as well.
Bothwell is collaborating on this investigation with Dr. Alesandro Santin, Professor of Obstetrics, Gynecology and Reproductive Sciences, and Dr. Joann Sweasy, Professor of Therapeutic Radiology and of Genetics. Both are past WHRY Pilot Project Program-funded investigators. Sweasy, who has done much research on how genetic mutations result in cancer, used a 2009 Pilot Project Award grant to begin developing a mouse model of breast cancer that incorporates both the human immune system and tumor pathology — to optimize individual breast cancer therapies. Santin, working with Dr. W. Mark Saltzman, the Goizueta Foundation Professor of Biomedical Engineering and founding Chair of the Department of Biomedical Engineering, used a 2010 Pilot Project Award grant to develop a new way to combat ovarian cancer relying on ultra-tiny nanoparticles to target and destroy treatment-resistant tumors.
Development of the new uterine serous cancer model is one of the central aims of Bothwell’s study. Another key aim is to test a hypothesis that a subset of uterine serous cancer patients have particular genetic mutations that have a protective effect in some patients.
In previous work, Dr. Santin and his colleagues demonstrated that approximately 8 percent or about one of every 12 uterine serous cancer patients have particular genetic mutations that appear to confer this protective effect. These patients should not be treated with radiation therapy or chemotherapy so as to preserve the protective effect.
Now, in this first Naratil Pioneer Award study, Bothwell and his team will use the new model to begin determining how this protective effect might work. Understanding the mechanism of this protective effect will provide new avenues to develop optimal therapeutic strategies for uterine serous cancer, Bothwell said.
“One of the questions we want to answer is: how are these patients able to combat the disease?” “Are the immune cells of the patients with the protective effect different from the immune cells of patients who don’t have the protective effect?” Bothwell said.
“My goal here is to make enough progress quickly to turn this into a larger funded team effort,” he said. “It’s taken a long time for me to get this model off the ground. And that’s why Alessandro (Santin) is so valuable here,” he said. Santin is both a clinician and researcher. “He is really into this study from the standpoint of helping patients – and that’s the real goal.” Because uterine serous cancer spreads quickly, the evaluation and selection of therapies must be completed as rapidly as possible to benefit patients. The new laboratory model will allow the team to evaluate the effectiveness of new therapies or combination therapies much faster than would be possible in clinical trials with patients and with no adverse consequences.
Women’s Health Research at Yale’s new Wendy U. and Thomas C. Naratil Pioneer Award, established in 2013 through a generous endowment gift from the Naratils, a Yale College ’83 couple, expanded our Center’s annual Pilot Project Program to initiate and support never before undertaken investigations on women’s health and gender differences. Our Director Carolyn M. Mazure, Ph.D., emphasized that all Pilot Project Program studies selected for funding must demonstrate new approaches to major challenges in women’s health, and describe a clear path to implementation for clinical or public health benefit.
What distinguishes the Naratil Pioneer Award is that it is for investigations that are either highly inventive or close to a major breakthrough in advancing women’s health – where funding is needed to reach its aims.
“This inaugurual Naratil Pioneer Award investigation is just the kind of project we hoped for when the Naratils stepped forward – to tackle a major challenge in women’s health with a revolutionary new approach and a vision to translate findings as quickly as possible into improved treatments,” Mazure said. “We have Wendy and Tom to thank for allowing this kind of work to go forward.”