Molly McAdow, MD, PhD (2022 – 2025)
Award: SMFM/AAOGF Scholar Award
Site of Research: Yale University School of Medicine
Title: The Role of Plasminogen Inhibitors in Endothelial Dysfunction in Preeclampsia
Preeclampsia affects 8% of pregnancies worldwide and is characterized by widespread endothelial dysfunction. There is no specific therapy for preeclampsia. Nitric oxide is a critical vasodilatory substance produced in endothelial cells by endothelial nitric oxide synthase (eNOS). Chemical inhibition or genetic manipulation of eNOS in animal models causes hypertension in pregnancy. Recent work by our laboratory has identified that exogenous plasminogen activator inhibitor 1 (PAI-1) physically interacts with and inhibits eNOS in endothelial cells. Maternal plasma PAI-1 levels rise over the course of normal pregnancy and increase more rapidly and to a greater extent in pregnancies affected by preeclampsia. PAI-2, a structurally similar molecule, is not found in plasma of non-pregnant individuals but is abundant in the third trimester of normal pregnancies. Interestingly, its circulating levels are suppressed in preeclampsia.
Predicated on these observations is the hypothesis that the interactions between PAI-1, PAI-2, and eNOS contribute to the pathogenesis of preeclampsia. We will investigate this hypothesis by defining the mechanisms of PAI-1-dependent eNOS inhibition and will use a translational approach to investigate whether these interactions could contribute to the maternal syndrome of preeclampsia. Second, we will explore whether PAI-2 interacts with or inhibits eNOS using biochemical and imaging approaches. Lastly, we will investigate whether these interactions are involved in the origins of preeclampsia at the maternal-fetal interface. Elucidating the activities of PAI-1 and PAI-2 and their interplay in pregnancy will help to better understand the molecular mechanisms of hypertensive disorders of pregnancy and may lead to novel therapeutic targets.
Robert Hillman, MD, PhD (2022 – 2025)
Award: GOG Foundation /AAOGF Scholar Award
Site of Research: MD Anderson Cancer Center
Title: Liquid Biopsy Detection of Structural Variant Breakpoints to Monitor Ovarian Cancer Clonal Evolution
It has long been known that ovarian cancers shed portions of their DNA into the bloodstream of affected women, and that sensitive methods can be used to detect this tumor DNA from blood samples. The research proposed in this study will develop a novel method for individually detecting rare populations of tumor cells from the bloodstream of women with ovarian cancer in order to longitudinally detect tumor evolution in real-time. This approach will rely on a key observation that the genomes of ovarian cancer are frequently rearranged, meaning each tumor has numerous “breakpoints” from two or more distant locations that are brought together. Since these “breakpoints” both identify tumor cell sub-populations and by definition do not occur in normal cells, the key insight of this proposal is that “breakpoint” detection from blood samples is an innovative and powerful approach to detecting ovarian cancer tumor evolution from blood samples.
This research has the potential to result in a completely new paradigm for monitoring ovarian cancer response to treatment. Rather than waiting for treatment completion to assess response, a woman and her doctor could observe her tumor’s evolution in real-time and personalize treatment decisions based on this information. The early detection of emerging tumor resistance could lead to earlier changes in treatment and improvement in survival outcomes. Importantly, this novel approach to monitoring tumor evolution is a broadly applicable technology that could be used across tumor types.
Shuk On Annie Leung, MD (2022 – 2025)
Award: AAOGF/ABOG Scholar Award
Site of Research: McGill University Health Centre
Title: Development of a Point-of-Care Ultrasensitive Assay for the Identification of High-Grade Cervical Dysplasia and Cervical Cancer
Cervical cancer is the fourth most commonly diagnosed cancer among women worldwide. With the discovery that human papillomavirus (HPV) is the primary cause of cervical cancer, many screening programs are transitioning to primary HPV testing because of its enhanced diagnostic sensitivity and less resource-intensive nature. However, HPV testing is less specific at detecting cervical cancer than Pap smears, resulting in unnecessary colposcopy referrals and overtreatment of non-cancerous lesions. While recent advances have identified protein biomarkers with improved specificity that could be used to complement HPV testing, standard protein-detection equipment is restricted to specialized laboratories. Collectively, this illustrates a need for an accessible and improved screening strategy to triage HPV-positive patients at highest risk of cervical cancer, which forms the basis of my research program. A panel of protein biomarkers that is sensitive and specific for cervical dysplasia and cancer will be identified using the ultrasensitive protein detection method of Single Molecule Array (Simoa). Next, to increase accessibility of the Simoa technology, it will be translated onto a portable point-of-care (POC) device by leveraging on existing microfluidic engineering technology. Finally, the design of the proposed POC device will be informed by the iterative ‘systems design engineering process’, which is built upon feedback collected during interviews and focus groups with stakeholders. Whereas laboratory-based protein detection is well-established, our solution would represent the first-of-its-kind device that leverages microfluidics-based engineering to enable improved and accessible detection of cervical sample biomarkers.
Courtney Townsel, MD MSc FACOG (2021-2024)
Site of Research: University of Michigan
Title: Placental Epigenetic Regulation of Fetal Opioid Exposure
The opioid epidemic in the United States is a devastating public health crisis, with increasing prevalence, particularly among pregnant women. Rates of opioid use disorder (OUD) in pregnancy have quadrupled over the past decade and have significant health implications for both the mother and neonate. The standard of care for OUD is medication assisted treatment with agents such as methadone or buprenorphine. These medications are used in pregnant women; however, we know little about how they are transferred by the placenta or the epigenetic factors that contribute to fetal exposure. Placental drug transporters, cytochrome p450 enzymes, and opioid receptors likely play a key role in fetal exposure to substances. The placental ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, are key in placental efflux of methadone from the fetus to the mother and are upregulated in the presence of methadone and buprenorphine. CYP19A1 is the major enzyme responsible for metabolizing both methadone and buprenorphine in the human placenta. Differential methylation in the promoter region of the opioid receptor mu 1 is associated with more severe NOWS. Through this research, we seek to understand how epigenetic regulation in the placenta of ABC transporters, p450 enzymes, and opioid receptors affects fetal exposure to methadone and buprenorphine.
Dr. BJ Rimel (2020-2022)
Award: 2020 GOG Foundation/AAOGF Clinician Scientist Award
Site of Research: Cedars-Sinai Medical Center
Title of Research: Olaparib and Durvalumav in Recurrent Progressive Endometrial Cancer: A proposal for a Novel Arm of the Platform Study, NRG GY012
Despite emerging treatments in endometrial cancer, most women with advanced stage or recurrent endometrial cancer will ultimately succumb to their disease. Common genomic events occurring in endometrial cancer include genes associated with DNA damage repair. Recent data shows that these weaknesses can be exploited with agents the limit the ability of the cancer cell to repair itself. Immunotherapy treatments in endometrial cancer have demonstrated efficacy in a specific population of tumors with another weakness, microsattelite instability. The combination of two agents to manipulate these features was demonstrated as safe in a phase 1 study of olaparib and durvalumab. Our overarching hypothesis is that women with endometrial cancer (EC) will derive more benefit from rationally designed drug combinations including DNA repair targeting agents and immunotherapy than from single agent therapy alone. We have designed a randomized phase 2 study that includes this combination as part of a larger NRG Oncology study. NRG GY012 is the first platform study in endometrial cancer and the inclusion of the olaparib and durvalumab arm represents a data driven approach to clinical trial development.
Dr. Floor Backes (2020-2022)
Award: 2020 GOG Foundation/AAOGF Mentored Clinician Scientist Award
Site of Research: The Ohio State University
Title of Research: Phase I/II study of Lenvatinib, Pembrolizumaband weekly Paclitaxel for recurrent Endometrial, Epithelial Ovarian, Fallopian tube and primary Peritoneal cancer
Although response rates to pembrolizumab were very promising in the mismatch repair deficient population (57%), in patients with microsatellite proficient (pMMR) recurrent endometrial cancer response rates were only 13%. Similarly, single agent lenvatinib did not demonstrate significant activity in recurrent endometrial cancer, however, the combination was recently granted FDA approval for treatment of recurrent pMMR endometrial carcinoma (EC). Activity of pembrolizumab has also been seen in recurrent ovarian cancer (ORR 11.5%). Although single agent activity is relatively low, combination therapy with other agents is more promising. Taxanes have significant single agent activity in ovarian and EC. Our group conducted a phase I study of weekly paclitaxel with lenvatinib in recurrent EC and recurrent ovarian cancer with very encouraging response rates, duration of response and PFS. In order to further improve this, we propose adding pembrolizumab to weekly paclitaxel and lenvatinib. We believe that this will provide synergy as taxanes have been demonstrated to upregulate PD-1 and PD-L1 in preclinical studies, increased CD8+ tumor infiltrating lymphocytes, and activated NF-kB signaling. Thus, we hypothesize that the addition of pembrolizumab to weekly paclitaxel and lenvatinib is safe with manageable toxicities and highly effective in patients with recurrent endometrial cancer and recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer. We will conduct a phase II clinical trial with safety lead in to determine objective antitumor activity of weekly paclitaxel, lenvatinib, and pembrolizumab in recurrent endometrial and platinum resistant ovarian cancer, safety and tolerability, and measure the progression free and overall survival in the study population. In addition, we will explore the baseline tumor genetic and microenvironment parameters predictive of clinical benefit or resistance to the treatment combination and potential mechanisms of resistance through circulating tumor DNA analysis, immune cell population analysis (CyTOF), and evaluation of the tumor microenvironment.
Bradley Corr, MD (2020-2023)
Award Type: AAOGF/ABOG
Title of Research: Classification of CTNNB1 Mutation for Biomarker Driven Treatment of Endometrial Cancer
Site of Research: University of Colorado
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)
Award type: AAOGF/SMFM Scholar
Title: Unknown, PTD and Microbiome as Biomarkers
Site of Research: University of Pennsylvania
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.
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.