2017 Research Fellowship
Drs. Laura Stabile, PhD & Timothy Burns, MD/PhD, University of Pittsburgh and the UPMC Hillman Cancer Center
Lung cancer is the leading cause of cancer death in women, killing more women each year than breast, uterine and ovarian cancers combined. Sex differences in non-small cell lung cancer (NSCLC) and survival suggest that estrogen plays a critical factor in the formation of tumors in women’s lungs.
Preclinical and epidemiological studies have demonstrated that the estrogen pathway is a driver of NSCLC progression in women. Results of this project will provide a mechanistic understanding of the role of estrogen on immune suppression and whether hormonal blockade can improve the response rate or durability of response in women with this type of cancer that are treated with targeted immunotherapy.
Dr. Laura Stabile
Laura Stabile, PhD is a Research Associate Professor in the Department of Pharmacology & Chemical Biology at the University of Pittsburgh and a member of the Lung Cancer Program at the UPMC Hillman Cancer Center. In addition to her research and teaching commitments, Dr. Stabile is an active member of the UPMC Women’s Task Force Committee, Clinical Protocol Review Committee, Animal Facility Advisory Committee, and the Cell and Tissue Imaging Facility Advisory Committee.
Dr. Stabile completed her undergraduate degree from Washington & Jefferson College and earned a Ph.D. in Biochemistry from West Virginia University. She completed her post-doctoral training at the University of Pittsburgh where she remained to continue her academic career as faculty.
For more than 15 years, her research efforts have focused on the role of growth factors and hormones in the development of upper aerodigestive tract malignancies with the overall goal of identifying effective targeted therapies for cancer treatment and prevention. During this time, she received multiple awards including the Flight Attendant Medical Research Institute Young Clinical Scientist Award, a Joan’s Legacy Foundation Award, a Lung Cancer Research Foundation Award as well as NIH support for her research. Preclinical laboratory findings have identified that estrogen signaling promotes proliferation in lung tumor preclinical models and have led to clinical trials examining the effectiveness of anti-estrogens combined with targeted therapies for advanced lung cancer.To date, her work has resulted in 43 peer-reviewed publications, 6 review articles and 4 book chapters. The proposed project seeks to expand on new preliminary data demonstrating hormonal regulation of the lung tumor micro-environment with the overall goal to test the efficacy of combining hormonal therapy with immunotherapy to inhibit estrogen signaling on both lung tumor cells and immune cells. As a translational research scientist with a strong interest in the clinical development of therapies to target the estrogen signaling pathway and further understanding lung cancer in women, she is excited about this project.
Dr. Timothy Burns
Dr. Timothy Burns, MD/PhD is an Assistant Professor of Medicine and Pharmacology & Chemical Biology at the University of Pittsburgh and a member of the Lung Cancer Program at the UPMC Hillman Cancer Center. As a physician-scientist and thoracic oncologist who has lost both of this parents to lung cancer and has an active weekly lung cancer clinic, he is personally and professionally committed to finding new therapies for his patients. Dr. Burns completed his undergraduate work at Cornell University and earned his MD degree and PhD degrees in Cell & Molecular Biology at the University of Pennsylvania. He completed his internal medicine residency and hematology-oncology fellowship at Johns Hopkins Hospital, Johns Hopkins School of Medicine. During his training, he received several prestigious awards, including the AACR-AstraZeneca Fellowship for Translational Lung Cancer Research and the ASCO Young Investigator Award. Since arriving at Pittsburgh in 2012, Dr. Burns has worked closely with the Hillman Cancer Center Lung Cancer Program to develop therapies for lung cancer. Dr. Burns continues to see lung cancer patients in the clinic, however, the majority of his time is spent in his research lab at the Hillman Research Pavilion. His focus is on characterizing key signaling pathways that are critical for the growth of non-small cell lung cancer and to develop novel targeted therapeutic approaches in KRAS-mutant non-small cell lung cancer and other oncogene driven lung cancers. Dr. Burns has received funding from the American Lung Association, the V Foundation, the LUNGevity Foundation, the Sidney Kimmel Foundation for Cancer Research and the Doris Duke Charitable Foundation. To date, Dr. Burns has published 49 cancer related publications. Dr. Burns has worked closely with Dr. Stabile on targeting estrogen signaling in lung cancer and is committed to exploring the combination of fulvestrant and durvalumab in the clinic and developing biomarkers to predict the patients who are likely to respond in hopes of improving survival in women with lung cancer.
Lay Progress Reports: Targeting female sex hormones to improve anti-tumor immunity – Laura P. Stabile, PhD/Timothy F. Burns, MD/PhD
November 2019:
We are pleased to report the continued progress by our multidisciplinary research team in understanding how the female sex hormone, estrogen, promotes a pro-tumor immunosuppressive lung tumor microenvironment that allows the tumor to evade the immune system and whether we can improve the activity of immunotherapy using anti-estrogens.
We have made significant progress in the first 18 months of funding. We have fully optimized our orthotopic mouse model that allows for lung tumor growth directly in the lung and have comprehensively characterized the immune infiltrate. Importantly, we have optimized the conditions to express both luciferase and green fluorescent protein in our lung cancer cells for effective quantitation of both primary tumor and metastatic spread by in vivo and ex vivo imaging. We have shown that dual therapy with the anti-estrogen fulvestrant and an anti-PD-L1 agent decreases the ability of lung cancer cells to metastasize and grow in the lungs and are ready to test this treatment regimen in the orthotopic setting. In addition, we have now identified macrophages as one of the key immune cells to target with anti-estrogen therapy to improve response to immunotherapy in mice and we are now exploring the role of these macrophages in our human samples using malignant pleural effusions (MPEs) obtained from lung cancer patients. Identifying the key immune cells responsible for the effects of anti-estrogens is an important milestone in our research. This will allow us to follow the key immune cells in our future clinical trial so that we can predict who will respond to this combination.For our proposed human studies, we have significantly increased our capacity to collect biospecimens and data from from lung cancer patients treated with immunotherapy at the UPMC Hillman Cancer Center that will be used for analysis of hormonal markers. Very shortly we will have enough patient samples and follow up to examine markers of the estrogen pathway in patients that respond or fail to respond to immunotherapy. Further, we have preliminary data on immune cell expression using multiplex staining and quantitation on patient tumor specimens. Finally, we have established new scientific collaborations both within and outside our institution to achieve these goals. Together these results further support our ultimate goal of bringing this combination to the clinic.
The review article entitled, “The estrogen pathway as a modulator of response to immunotherapy” was published in the September 2019 issue of Immunotherapy.
Results of this project will provide the preclinical rationale for testing the combination of an anti-estrogen and immune checkpoint blockade in the clinic to improve the efficacy of immunotherapy in women with lung cancer. We may also identify patient subsets in which hormonal/immune checkpoint agents could be particularly effective which may help explain sex-specific differences in lung cancer.
We would like to thank all the “A Breath of Hope” donors who have contributed to support our research efforts focused on female-specific lung cancer. Your generosity brings us one step closer to understanding factors involved in risk and outcome of lung cancer among women and to understanding of the role of estrogen in anticancer immunity
November 2018:
We are pleased to report progress by our multidisciplinary research team in understanding how the female sex hormone, estrogen, promotes a pro-tumor immunosuppressive lung tumor microenvironment that allows the tumor to evade the immune system and whether we can improve the activity of immunotherapy using anti-estrogens. Since our project was funded, there has been even further rationale for our studies including published reports that female lung cancer patients who receive immunotherapy do not benefit from this therapy as much as male lung cancer patients. This sex-dependent difference in reduced immunotherapy efficacy highlight the importance of further interrogation of the mechanistic basis for these observations, especially since female lung cancer patients generally have better survival than male patients.We have made significant progress in the first 6 months of funding. First, we have modified our preclinical approach to use a more physiologically relevant mouse model that allows us to grow our novel tobacco carcinogen-induced lung tumor cells directly in the lung. Second, we have generated new data showing that dual therapy with the anti-estrogen fulvestrant and an anti-PD-L1 agent can decrease the ability of lung cancer cells to metastasize and grow in the lungs. This further supports our ultimate goal of bringing this combination to the clinic. Finally, we have optimized our assays and endpoints for our human studies and preliminary studies suggest that we can modulate the type of immune cells that are present in the tumor with anti-estrogen treatment.Results of this project will provide the preclinical rationale for testing this combination in the clinic to improve the efficacy of immunotherapy in women with lung cancer. We may also identify patient subsets in which hormonal/immune checkpoint agents could be particularly effective which may help explain sex-specific differences in lung cancer. Dr. Stabile was invited to give an oral presentation of this work at the 8th Great Lakes Nuclear Receptor Conference held at the Masonic Cancer Center in Minneapolis, Minnesota in October.
April 2019:
We are pleased to report the continued progress by our multidisciplinary research team in understanding how the female sex hormone, estrogen, promotes immune suppression in the lung tumor micro-environment that allows the tumor to evade the immune system and whether we can improve the activity of immunotherapy using anti-estrogens.
We have made significant progress in the first 12 months of funding. We have fully optimized our mouse model that allows for tumor growth directly in the lung and have comprehensively characterized the immune infiltrate. Importantly, we have optimized the methodology for tracking the tumor growth in the mice to quantify both primary tumor and metastatic spread by using fluorescence and luminescence imaging. We have shown that dual therapy with the anti-estrogen, fulvestrant, and an FDA approved immunotherapy agent decreases the ability of lung cancer cells to metastasize and grow in the lungs and are ready to test this treatment regimen in the orthotopic setting. For our proposed human studies, we are actively collecting bio-specimens and data from from lung cancer patients treated with immunotherapy at the UPMC Hillman Cancer Center that will be used for analysis of hormonal markers. Further, we have data showing that we can use a novel tool to simultaneously characterize the different immune cells within the tumor micro-environment and their spatial relationship to one another. Finally, we have established new scientific collaborations both within and outside our institution to achieve these goals. Together these results further support our ultimate goal of bringing this combination to the clinic.
Results of this project will provide the preclinical rationale for testing the combination of an anti-estrogen and immune checkpoint blockade in the clinic to improve the efficacy of immunotherapy in women with lung cancer. We may also identify patient subsets in which hormonal/immune checkpoint agents could be particularly effective which may help explain sex-specific differences in lung cancer.
Dr. Stabile presented this work at the 8th Great Lakes Nuclear Receptor Conference held at the Masonic Cancer Center in Minneapolis, Minnesota in October 2018 as well as at multiple institutional venues. Drs. Burns and Stabile have submitted a review article entitled, “The estrogen pathway as modulator of response to immunotherapy” to the journal Immunotherapy.