American Association of Obstetricians and Gynecologists Foundation

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Current Scholars

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.
 


Jennifer Gilner – (2016-2019)
Award: Pregnancy (SMFM) Foundation/AAOGF Scholar
Site of Research: Duke University
Title of Research: The Role of Regulatory T Cells in the Maternal-Fetal Rejection Phenotype of Preterm Birth.

Pregnancy represents a unique natural allograft scenario in which immunologically mismatched organisms must tolerate direct apposition, yet maintain immunologic activity against external pathogens. This is analogous to organ transplantation, where tolerance of the grafted organ (and its foreign antigens) requires active regulation of immune responses. T Regulatory cells (or “Tregs”) are a unique subpopulation of CD4+ lymphocytes that play a critical role in establishing immune tolerance and therefore preventing allograft rejection. In the case of pregnancy, the fetus represents a foreign graft, and immune rejection may lead to adverse pregnancy outcomes such as preterm birth. Given the biologic parallels between organ transplantation and pregnancy, we hypothesize that Tregs play a parallel role in pregnancy; specifically to induce tolerance in the mother, and prevent rejection which could lead to preterm birth. To date, regulatory T cell function has only been studied in the broadly defined “spontaneous” or “medically indicated” preterm birth cohorts. We propose to focus on the cohort of preterm births with a molecular phenotype of maternal anti-fetal rejection, given that Treg suppressive function is well established as a critical mechanism in maintenance of alloimmune tolerance. This innovative approach will allow for a careful characterization of the molecular immunology of affected pregnancies, and will be critical to the development of targeted detection and treatment strategies for reducing the burden of preterm birth.

Jose Alejandro Rauh-Hain – (2016-2019)
Award: American of Obstetrics and Gynecology/AAOGF Scholar
Site of Research: Massachusetts General Hospital
Title of Research: Trends in First-line Treatment and Spending on Care for Women with Epithelial Ovarian Cancer

The United States spends over US $2.2 trillion (16% of national budget) on healthcare. In particular, cancer treatment accounts for an increasing amount of national health expenditures; including rising costs of new chemotherapy/biologic agents. In this context, cost analysis is paramount in order to measure the disease-specific economic burden and predict the impact of novel medical interventions. The costs associated with cancer treatment must consider both the costs of treatment but also the cost of managing disease progression or recurrence as well as the cost of treatment-related toxicity. Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. Despite the fact that ovarian cancer is the most lethal gynecologic malignancy, little information is available about the cost of treatment after the diagnosis of ovarian cancer. Ovarian cancer treatment in particular is susceptible to rising costs due to the constant influx of novel chemotherapeutics and biologics, most of which are more costly than the established front-line therapies but have limited proven benefit. The costs associated with care of ovarian cancer patients are considerable and are highest during the first year of diagnosis and the last year of life. The overall objective of this project is to determine the direct medical cost of primary ovarian cancer treatment and related complications, and to estimate contribution of different therapeutic modalities and health care services to total spending on ovarian cancer care using the Premier Perspective database.
 


Malgorzata E. Skaznik-Wikiel, MD (2015-2018)
Award: ABOG/AAOGF Scholar
Site of Research: University of Colorado Denver, Anschutz Medical Campus
Title of Research: Obesogenic lipid alterations as a mechanism of impaired fertility

Obesity is a daunting medical problem worldwide. Recent studies have shown that 68% of adults are overweight and around 36% are obese in the United States. Obesity is associated with multiple adverse effects on female reproduction, including anovulation, irregular menses, infertility, miscarriage, and increased risk to develop a range of pregnancy complications. Although weight loss has been reported to increase conception and live birth rates in obese women in retrospective studies, no intervention to-date has consistently normalized clinical pregnancy rates in obese women. Inflammatory responses appear to play a crucial role in impaired oocyte quality and decreased ovarian reserve associated with obesity and high-fat diet (HFD). The overriding objective of this proposal is to clarify mechanisms associated with obesity-induced ovarian dysfunction using wild type and transgenic mouse models and different diets to further our understanding of mechanisms. We plan to test if HFD-induced obesity, rather than exposure to HFD without the obese phenotype, causes impaired fertility. We hypothesize that HFD impairs fertility only in the presence of obesity. We also plan to test if cholesterol rich high-fat/high-sugar (HF/HS; Western-style) diet is more detrimental to ovarian function than diet rich in fat alone, and if phenotype (obese vs non-obese) plays a role in influencing ovarian function. We hypothesize that HF/HS diet is more detrimental to ovarian function than HFD alone, especially in the presence of obesity. Finally, we plan to elucidate if the circulating ratio of omega-3 to omega-6 fatty acids explains ovarian lipotoxicity in HFD-induced obesity. We hypothesize that specific combinations of circulating polyunsaturated fatty acids (PUFAs) play a role in the development of diet-induced ovarian dysfunction and subsequent impaired fertility. Specifically, we will test if the omega-3 to omega-6 fatty acid ratio has a beneficial effect on ovarian function, even in obese animals. We will use the obese Fat-1 transgenic mouse model that maintains a healthy excess of omega-3 PUFAs regardless of diet and focus on their pro-inflammtory/anti-inflammatory cytokine profile in relation to fertility status. Clarifying the pathways that lead to obesity-related subfertility on a molecular level will lay the groundwork for the development of interventions that can be used for prevention of the reproductive consequences of obesity and high-fat diet.
 

K. Joseph Hurt, MD PhD (2015-2018)
Award: Pregnancy (SMFM) Foundation/AAOGF Scholar
Site of Research: University of Colorado, Anschutz Medical Campus
Title of Research: Hydrogen sulfide regulation of myometrial contractility and parturition

Preterm birth is a frequent and costly obstetric outcome, but the molecular program of parturition and contribution of specific quiescence factors is not completely understood. Hydrogen Sulfide (H2S) is a small gaseous signaling molecule, similar to nitric oxide. It is a potent in vitro uterine tocolytic, produced widely in the developing fetus, placenta, and myometrium. The role of H2S in parturition signaling and fetal development is unknown. We found surprising changes in the enzymes that produce endogenous H2S in various rodent models of preterm and term labor induction, but the upstream signals that control H2S production during gestation and downstream signaling pathways remain to be characterized. We hypothesize that H2S may represent a novel target for preterm birth prophylaxis or for fetal therapy, and aim to identify the targets of H2S in myometrial and fetal physiology. We use physiologic, molecular, and pharmacologic approaches along with knockout and transgenic mouse models, to define the role of H2S in pregnancy and delineate its mechanisms in parturition and development. Ultimately, we hope our work will lead to new therapies to prevent preterm birth and the complications of prematurity.

Rebecca C. Arend, MD  (2015-2018)
Award: American Board of Obstetrics and Gynecology/AAOGF
Site of Research: University of Alabama at Birmingham Department of Obstetrics and Gynecology
Title of Research: Treatment of Ovarian Cancer with WNT/B-catenin inhibitors

Advances in surgery and chemotherapy have improved ovarian cancer patient responses and increased their time in remission, but cure rates have not significantly changed in the last 20 years and the majority of patients eventually recur. Cancer stem cells are a small population of cells that remain in the body after most patients are cancer free for a period of time after their primary treatment, which are resistant to chemotherapy and cause recurrence. This population makes up only about 1-5% of the tumor, but has been shown to reform a complete tumor in mouse models. It continues to change in genetic make-up, metabolism, and proteomics with each treatment of chemotherapy. There are many metabolic pathways that are involved in the growth of these cells, which include the Wnt pathway, mTOR/STAT3 pathway, and NFkB pathway. It is not known how to target multiple “stem cell pathways” at one time so that the cancer stem cells are sufficiently killed. One anti-helminth drug, niclosamide, which has been FDA approved and used for over 50 years, has been shown to inhibit all three of these pathways. The exact mechanism is still unknown. The bioavailability of the drug may not be sufficient to kill cancer stem cells; therefore, I have collaborated with an organic chemist at Ohio State who has developed analogs to this drug that potentially have better bioavailability. I also have a specific Wnt-inhibitor made by Novartis in the lab that is already in a phase I trial that I am doing both in vitro and in vivo work with.

By collecting cancer tissue from patients at the time of their first surgery and then again at any additional surgeries they may have after getting treated with chemotherapy we have the ability to analyze the genetic and molecular changes in the tumor that can help us further develop targeted therapies for this population. Ascites is the fluid that develops in the abdominal cavity of patients usually at the time of primary diagnosis and represents a population of metastatic cells that can also be collected at the time of initial diagnosis. In addition patients frequently have ascites that causes discomfort in their final weeks of life, and get this fluid removed for symptomatic relief. Cells can be collected from the ascites at this time, which is usually cells that have become resistant to multiple lines of chemotherapy, so is an excellent model to use in further investigating the molecular changes that occur with chemoresistance. Both the tissue and the ascites can be implanted into mice to develop patient derived xenograft models that can be used for both drug development and molecular analysis. We have also discovered a way to implant chemo-responsive cells from patients into mice, treat them with chemotherapy and develop a chemo-resistant model from the same patient. By maintaining this tissue and ascites bank in addition to maintaining PDX patient-derived xenograft models this allows us also to collaborate with many other labs at UAB who are doing research on other cancers and expand this research to ovarian. In addition, there a several types of rare endometrial cancer that is as aggressive, if not more aggressive than ovarian cancer, which I intend to also collect tissue and analyze for potential targeted agents. This collection of samples, and data, allows us also to collaborate with drug discovery labs and companies to do pre-clinical research for solid tumors.
 

AAOGF News

2016 Bridge Grant Recipients

Jason Bell, MD, MPH, MS
Sawsan As-Sanie, MD, MPH
Angeles Secord, MD, MHSc

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2016 Travel Award Recipients

Vivian Sung, MD
Jennifer M. Wu, MD, MPH
Charles A. Leath, III, MD, MSPH
Ginny L. Ryan, MD
Michael T. McHale, MD, FACOG
Micah J. Hill, MD
Scott Allan Sullivan, MD, MSCR, FACOG
Michael J. Goodheart, MD
Aaron Kyle Styer

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