Women’s Health Research at Yale (WHRY) today announced research awards aimed at identifying biomarkers for early detection of ovarian cancer, developing a delivery system for antibiotics to combat intra-amniotic infection, and determining how sex and gender affect the diagnosis and management of thoracic aortic disease.
“All three projects are focused on areas of pressing need in women’s health,” said WHRY Director Carolyn M. Mazure, PhD, the Norma Weinberg Spungen and Joan Lebson Bildner Professor in Women’s Health Research.
Developing Diagnostics for Early Detection of Ovarian Cancer
When ovarian cancer is diagnosed at an advanced stage, it has the highest rate of mortality of all types of gynecologic cancer. However, few biological markers are available to screen for ovarian cancer and their effectiveness is limited.
This year’s Wendy U. and Thomas C. Naratil Pioneer Award will provide Stacy Malaker, PhD, Assistant Professor of Chemistry, with the opportunity to pursue a novel approach to identifying “biomarkers” that can detect ovarian cancer at an early stage.
The focal point of her research is on the sugar molecules or “glycans” that coat the outside of all cells. In a normal process known as glycosylation, these sugars attach to the amino acids in a protein to create a glycoprotein. Glycoproteins are essential in maintaining our immune systems, and errors in the glycosylation process can allow a tumor cell to evade our immunity defenses.
One such glycoprotein, Mucin 16, coats the epithelial cells that line internal body surfaces and protects these cells from pathogens such as cancer. If the glycosylation process that produces this protection is flawed or changed, the anti-cancer immune protection could be lost, which then allows cancer to form, progress, and metastasize.
Dr. Malaker is searching for a biomarker that signals the early detection of ovarian cancer by identifying a change in the Mucin 16 glycosylation process known to promote cancer development. Moreover, she will investigate what occurs during the glycosylation process that allows cancer to penetrate the immune system’s defenses using patient samples. Previous research has shown that after cancer invades a cell, Mucin 16 on that cell is shed into the bloodstream. The shed version is called CA125 and is one of the only known ovarian cancer biomarkers. Dr. Malaker’s goal is to determine how and why the glycan patterns change on shed CA125 in order to develop a method to detect cancer earlier.
“This award is incredibly exciting because it will allow my laboratory to delve into a project that is important to me on a personal level and to many women worldwide. Successful completion of the aims within this pilot grant could be transformative for those who are at risk for ovarian cancer,” said Dr. Malaker.
Using Nanoparticles to Treat Infection and Improve Pregnancy Outcomes
One of the leading causes of premature delivery during pregnancy is intra-amniotic infection (IAI). This occurs when bacteria infect the placenta, the amniotic fluid, and the membranes that line the uterus and maintain the structure of the amniotic sac. Once IAI has been diagnosed, delivery must occur rapidly as the infection puts stress on the fetus, leading to an elevated heart rate and the risk of fetal heart failure. However, infants with premature delivery can face increased risk of both short and long-term health challenges.
David Stitelman, MD, Associate Professor of Pediatric Surgery and Obstetrics, Gynecology, and Reproductive Sciences, is being awarded a two-year WHRY Pilot Project grant to assess a novel system that delivers antibiotics to the amniotic space and treats the infection, allowing the pregnancy to continue.
One of the biggest challenges historically to treating IAI before delivery has been getting antibiotics to the infected area surrounding the fetus. Mothers can be given antibiotics at the time of diagnosis, but the medication is unable to penetrate the gel-like biofilm barrier which surrounds the fetal space.
Working alongside collaborators W. Mark Saltzman, PhD, Goizueta Foundation Professor of Chemical and Biomedical Engineering, and Vikki Abrahams, PhD, Professor of Obstetrics, Gynecology and Reproductive Sciences, Dr. Stitelman is studying the use of biodegradable synthetic particles called nanoparticles, which are about the size of the head of a pin. These nanoparticles can pass through the biofilm and deliver the antibiotics directly to the amniotic fluid, membranes, and placenta.
These nanoparticles, which are made of FDA-approved materials, can be tailored to ensure they do not break down in the biofilm and release the correct dose of antibiotics. Dr. Stitelman and his team have established a three-step plan to assess the efficacy of this technique. They will first develop a nanoparticle that is stable and can feasibly deliver the proper dose of medication. Then, they will ensure that the nanoparticle and its application behave as expected in ex-vivo human amniotic fluid. Finally, they will confirm the technique is effective in treating the infection.
“The outcomes for very small premature babies, especially those impacted by pregnancy related infections, are unacceptably poor, which makes pregnancy the most logical time to intervene,” Dr. Stitelman said. “My lab has already found research success using nanoparticles to provide therapeutic agents to the fetus. Now we are looking to this therapy to improve the health of the tissues that support pregnancy.”
If successful, the research team will be well positioned to continue trials on the path to a new treatment for IAI and to improving the health of mothers and children.
Investigating Sex and Gender Based Disparities in Diagnosis and Outcomes of Thoracic Aortic Disease
Thoracic aortic disease occurs when the walls of the aorta, the main chest artery that carries blood from the heart to the rest of the body, begin to weaken and cause the artery to widen. If the artery becomes too wide, it can rupture or tear resulting in a life-threatening aortic aneurysm. The condition is responsible for significant morbidity and mortality, especially in women compared to men. Moreover, it has been observed among clinicians that thoracic aortic disease presents differently in women, but scientific study of these differences is limited.
Roland Assi, MD, Assistant Professor of Cardiac Surgery, is being awarded a WHRY pilot project grant to advance early detection of thoracic aortic disease as well as investigate both biological and social determinants of why women with this disease face poorer health outcomes than do men. The widening process of the aorta is slow and can often be managed with diet, lifestyle changes, and routine surveillance if it is detected. However, understanding who is at risk is difficult because signs and symptoms of the disease can be difficult to diagnose until there is a rupture.
Dr. Assi’s research will include determining how the symptoms of the disease appear in women compared to men, and how women-specific conditions like pregnancy, menopause, and hormone therapy affect the disease. In addition, he will examine whether women receive referrals to specialists or are given plans to monitor and manage the disease in a less timely manner than men.
“In my clinical practice I noticed that many women with thoracic aortic disease were arriving in a worsened condition because they were not accurately diagnosed. This pilot project grant is important to help us understand the magnitude of disparity in this disease and increase its awareness among women,” Dr. Assi said.
With a greater insight into how this disease affects women and men differently, health care providers will be able to enhance clinical decision making and care to improve the health and well-being of all people with thoracic aortic disease.