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
Lay Progress Report: Laura P. Stabile, PhD/Timothy F. Burns, MD/PhD
Targeting female sex hormones to improve anti-tumor immunity
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.