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Current Scholars

Bradley Corr, MD (2020-2023)
Title of Research: Classification of CTNNB1 Mutation for Biomarker Driven Treatment of Endometrial Cancer

Over the past ten years endometrial cancer incidence and mortality rates have unfortunately been on the rise despite significant advances in the science and patient care. However, our entire thinking of endometrial cancer has recently shifted away from the bi-modal type I vs type II model and into the molecular based model of genomic classification. Precision based medicine is now guiding our treatment algorithms for this malignancy. CTNNB1 mutation, which activates the Wnt/b-catenin pathway, has been described as a potential biomarker signifying a subclass of tumors with worse outcomes in patients who have historically been thought of as having a low risk of recurrence. Our objective is to validate the role of CTNNB1 as a prognostic biomarker, develop an accurate detection method using IHC, and evaluate targeted therapies for development of a clinical trial. Utilizing next-generation sequencing (NGS) and IHC analysis of a large national databank of tumors, we will validate the role of this mutation in an outcomes analysis and identify the most accurate detection methods for population-based evaluation. Furthermore, we will analyze multiple approaches to Wnt/b-catenin inhibition with the goal of developing a small molecule inhibitor into clinical trial utilizing CTNNB1 as the biomarker. Ultimately, we hope to develop a clinical trial for biomarker driven therapy in endometrial cancer utilizing CTNNB1.
 


Kristin D. Gerson, MD, PhD (2020-2023)

Sequelae of prematurity remain the leading cause of neonatal morbidity and mortality worldwide. Despite efforts to reveal underlying etiologies of spontaneous preterm birth, major knowledge gaps persist. Newer data support the concept that premature cervical remodeling may function as an initiator of early parturition. Yet, what triggers premature cervical remodeling remains unknown. Recent studies have demonstrated strong associations between non-optimal cervicovaginal microbiota and spontaneous preterm birth. It is hypothesized that cervicovaginal microbiota can trigger cervical remodeling. Providing a potential mechanism for these observed associations, microbial supernatants from some of the same bacterial taxa found to be associated with spontaneous preterm birth in the human cohort can induce cervicovaginal epithelial disruption. In other biologic systems, microbial metabolites serve as the key regulators of epithelial and mucosal compromise. A recent study from our institution revealed that cervicovaginal metabolomic output among women with high-risk microbiota can distinguish those who have spontaneous preterm birth versus term birth. No studies to date have examined mechanisms through which microbial metabolites in the cervicovaginal space may trigger or protect against spontaneous preterm birth. We propose to elucidate microbiome-metabolome interactions governing cervicovaginal epithelial disruption and premature cervical remodeling through in vitro and in vivo metabolomic experimental approaches. Select microbial metabolites may not only serve as more accurate predictive biomarkers for spontaneous preterm birth, but also carry potential as therapeutics in restoring or maintaining cervicovaginal health in pregnancy, thereby blocking the cascade of events that lead to aberrant cervical remodeling and spontaneous preterm birth.
 


Jacqueline Parchem, MD (2019-2022)
Award: SMFM/AAOGF Scholar
Site of Research: University of Texas
Title of Research: Modulation of Neural Tube Closure by Amniotic Fluid Exosomes

Neural tube defects (NTDs) are devastating birth defects that result from failure of neural tube closure during early fetal development. In spina bifida, trauma to the exposed spinal cord results in irreversible neurologic injury. Despite advances in fetal surgery, the majority of children remain unable walk and have lifelong disability. Therefore, innovative prenatal interventions have the potential to reduce residual deficits children with NTDs. To identify mechanisms governing neural tube closure and neural injury in NTDs, our study focuses on the role of amniotic fluid (AF) exosomes. Exosomes are naturally-occurring nanovesicles in the AF that facilitate cell communication through the exchange of molecular messages. While exosomes have been shown to be important for a number developmental and disease processes, the role of AF exosomes in fetal neurodevelopment is unknown. We will use a combination of in-depth molecular analyses of human AF samples and experiments in mice and cell culture to test our central hypothesis that AF exosomes modulate neural tube development and injury in NTDs. We will further test an innovative prenatal treatment strategy to determine the potential of exosome-based fetal therapy.
 


Mark Clapp, MD (2019-2022)
Award: American Board of Obstetrics & Gynecology/AAOGF Scholar
Site of Research: Massachusetts General Hospital
Title of Research: Development of an EHR-based Obstetric Risk Score

Accurate methods for risk stratification in obstetrics are essential to anticipate and prepare for potential intrapartum complications. Furthermore, risk stratification can help to ensure that patients are cared for by the appropriate provider and at the appropriate facility. Currently, few methods exist for risk stratification in pregnancy. This research project will use the vast data collected in the electronic health record (EHR) to predict severe maternal morbidity during labor and delivery. As EHR data are gathered in large quantities and in real-time by most health care institutions, the long-term goal for this research is to develop and incorporate EHR-based tools to aid in clinical decision-making and risk recognition for providers, ultimately reducing pregnancy-related morbidity and mortality.
 


Rebecca Previs, MD (2019-2022)
Award: GOG Foundation/AAOGF Scholar
Site of Research: Duke University
Title of Research: Immune Modulation of CaMKK2 in the Ovarian Tumor Microenvironment

The treatment of ovarian cancer includes a combination of surgery and chemotherapy. Although the majority of women initially respond to treatment, the likelihood of cancer progressing remains high. When this occurs, physicians treat patients with chemotherapy with modest success rates. An urgent need exists to treat ovarian cancer patients with better, lifesaving options when our current therapies are not enough. Often ovarian cancer cells, like other types of cancer, escape recognition by the bodies' natural defense system, the immune system. The immune system consists of multiple different cell types that assist in recognition of foreign cells, like cancer cells. Other cells, called T-cells, are devoted to attacking these foreign cells. In other tumor types, like melanoma, therapies are geared toward enhancing the way the immune system works to combat cancer cells. Clinical trials for this type of treatment or immunotherapy are ongoing for ovarian cancer patients. This study evaluates the role of CaMKK2, which has been observed overexpressed in the tumor cells of ovarian cancer patients whose cancer tends to recur sooner. It is also known to be expressed on several types of immune cells. We seek to modulate CaMKK2 and better understand its role within ovarian cancer and cancer-associated immune cells. The data generated by this proposal will provide the rationale for manipulating CaMKK2 in patients to make their immune system more effectively recognize foreign ovarian cancer cells, and consequently, make their cancer more responsive to therapies.
 


Nandini Raghuraman, MD (2018–2021)
Award: Foundation for SMFM/AAOGF Scholar
Site of Research: Washington University
Title of Research: Risks of intrapartum maternal oxygen supplementation: mechanisms for harm in the mother and neonate

Intrapartum oxygen (O2) supplementation for Category II fetal heart tracings is nearly ubiquitous on Labor and Delivery units, with over 60% of laboring women in the U.S. receiving supplemental O2 at some point during labor. This practice has become standard of care, yet there is no evidence of benefit and even concern for possible harm via free radical production. Hyperoxygenation in the neonate is associated with adverse outcomes such as retinopathy, bronchopulmonary dysplasia, and abnormal neurodevelopment. Similar harm has been demonstrated in adults including increased ICU morbidity from excess oxygen exposure. This calls for a closer look at the effect of intrapartum oxygen exposure on the fetus. We plan to conduct a randomized controlled trial of maternal oxygen supplementation versus room air in patients with Category II fetal heart tracings in labor. The primary objective of this study is to investigate the effect of intrapartum oxygen exposure on maternal and umbilical cord malondialdehyde, a free radical-mediated marker of oxidative stress. We will also collaborate with pediatric neurology to use magnetic resonance diffusion tensor imaging to study the effect of intrapartum hyperoxia on the neonatal brain.
 


Lauren Theilen, MD (2018–2021)
Award: American Board of Obstetrics & Gynecology/AAOGF
Site of Research: University of Utah Health/Intermountain Healthcare
Title of Research: Modifiable cardiovascular risk and cardiovascular morbidity following recurrent hypertensive disease of pregnancy

Women who have had hypertensive disease of pregnancy (HDP) in more than one pregnancy have significantly increased risks for death from heart disease and stroke before the age of 50; however, based on current guidelines, many of these women may not initiate screening for cardiovascular risk factors before age 45. We hypothesize that women with a history of recurrent HDP will develop detectable, modifiable cardiovascular risk factors within 10-15 years of their first affected pregnancy. To test this hypothesis, we will identify women with recurrent HDP who delivered their first affected pregnancy 10-15 years ago (exposed women) and match them to a group of women who also had more than one pregnancy, but who had no history of HDP in any of their pregnancies (unexposed women). We will screen both groups of women for modifiable cardiovascular risk factors, and we will compare the incidence of these risk factors among exposed and unexposed women. Women who are identified as having increased risk for cardiovascular disease will be referred to an appropriate healthcare provider for further evaluation and treatment. Additional information will be collected on an annual basis from subsequent visits to primary care providers to allow ongoing collection of data regarding cardiovascular risk and health outcomes. We will also perform a retrospective study using medical records to determine rates of cardiovascular disease (coronary artery disease, myocardial infarction, and stroke) among women with a history of recurrent HDP. Our study will provide much-needed information that may inform new screening strategies to improve long-term health among women.
 


Anne Van Arsdale, MD, MSc (2017-2020)
Award: American Board of Obstetrics and Gynecology/AAOGF
Site of Research: Montefiore Medical Center/Albert Einstein College of Medicine
Title of Research: Mapping HPV Integration in precancerous cervical lesions

Infection with a high-risk variant of human papilloma virus (HPV) is a well-established, key event in the development of cervical carcinoma. One consequence of HPV infection is expression of virally encoded oncogenes that drive cell proliferation, most notably those encoding the E6 and E7 proteins. Integration of the HPV DNA into the human genome is a second consequence that has recently emerged as a ubiquitous factor in tumorigenesis that 1) stably associates the viral oncogenes with a host cell, 2) likely drives expression of host oncogenes that flank the sites of HPV DNA insertions, and 3) also causes human genome instability. Identification of HPV DNA integration events early in the disease process and assessment of their impact on temporal progression of cervical dysplasia may provide potential risk stratification criteria for women at the time of incident screening. While use of next generation sequencing (NGS) methods have significantly advanced our understanding of the consequences of HPV DNA integration, understanding the precise patterns and potential consequences of integration, particularly in the early stages leading to cervical neoplasia, remains a significant void in our knowledge. A major, current, shortcoming in clinical management of early cervical dysplasia is the inability to assess which lesions will be among the small fraction that progress to full-blown, invasive neoplasia, thus precluding limiting treatments with significant morbidity risks to only those at substantial risk.

To fill this significant gap, we have developed a custom-designed hybridization capture NGS approach designed to enrich for HPV DNA and detect viral integration events present in only a small fraction of cells in early lesion tissue samples. In pilot data, our method has proved remarkably sensitive, identifying all previously validated integration sites in well-characterized cell lines, along with 3 fold novel integration sites in both cell lines and pre-invasive clinical samples. I hypothesize that integration of HPV DNA is a crucial step in progression of early lesions to full-blown, invasive carcinomas and that clonal expansion of cells with integrations adjacent to cellular oncogenes is a key marker of disease progression in precancerous CINs. Building on my results, I propose to study HPV integration events throughout the time course of disease, monitoring the spatio-temporal relationships of integration events and their clonal expansion from early stage cervical lesions to cervical cancer and to determine at the genome and transcriptional level the effects of integration events. To accomplish this, I will use samples in our clinically well-annotated tissue biorepository from women with incident cervical dysplasia or carcinoma who were followed longitudinally. The ultimate goal of this project is to identify integration events that help predict progression of cervical dysplasia, thus serving as a personalized biomarker in stratifying women at the time of screen screening.
 


Adetola Louis-Jacques (2017-2020)
Award: SMFM/AAOGF
Site of Research: University of South Florida Morsani College of Medicine
Title of Research: Lactation and Association with Maternal Gut Microbiome and Epigenetic Programming
 


 

AAOGF News

2019-20 Bridge Grant Recipients

Vanessa Dalton, MD, M.P.H.

Karen McLean, MD PhD

Richard Moore, MD, FACS, FACOG

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2019 Travel Award Recipients

Shannon Hawkins, MD
Indiana School of Medicine
AGOS President’s Award

Adetola Louis-Jacques, MD
University of South Florida
AAOGF President’s Award

Ann Van Arsdale, MD
Albert Einstein
Donald Swartz Award

Goje Tosin, MD
Cleveland Clinic
Henry L. Darner Award

Marc Parrish, MD
University of Kansas
J Bay Jacobs Award

Mostafa Borahay, MD
Johns Hopkins
James W. Kennedy Award

Sarah Osmundson, MD
Vanderbilt University
Walter T. Dannreuther Award

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