Clinical Significance and Mechanistic Insights into Ovarian Cancer Mitochondrial Dysfunction
Abstract
Epithelial ovarian cancer remains the most deadly gynecological malignancy to date, with a large proportion of patients eventually confronting recurrence and chemoresistance. Identification of the molecular basis of chemoresistant cancers and their therapeutic targeting are two of the biggest challenges facing clinicians and basic scientists trying to combat this deadly disease. The studies proposed herein attempt to directly address the vision and mission of the Ovarian Cancer Research Program by focusing on elucidating unique aspects of ovarian cancer etiology and chemoresistance. Our proposal is based on published and preliminary work from our laboratory that suggests a subgroup of chemoresistant epithelial ovarian cancers are marked by severe mitochondrial dysfunction. In addition, we have identified a potential candidate protein that may be mechanistically linked to these observations. Interestingly, high levels of this mitochondrial fission protein are found in a significant proportion of ovarian cancers. Since mitochondria and cell death in response to chemotherapy are intricately linked, we hypothesize that mitochondrial dysfunction and aberrations in mitochondrial fission are an underlying cause for chemoresistance observed in this unique subgroup of ovarian cancer cases. Our research team, comprised of both gynecologic oncologists and basic cancer researchers, will test the clinical relevance of our hypothesis in a cohort of ovarian cancer patient specimens and will carry out mechanistic studies to gain novel insights into the underlying causes of our observations using cutting-edge scientific techniques. In the short term, our work will verify the existence of this distinct subgroup of highly chemoresistant, mitochondria-defective ovarian cancers and determine the underlying biological mechanisms behind this phenotype. Based on preliminary and publicly available expression data, we estimate that this could affect as many as 25% of high-grade serous ovarian cancer patients. The proposed studies will not only provide new insights into the biology of ovarian cancer and explore novel mechanisms linking mitochondrial dysfunction with specific chemoresistance pathways, but will also test if this knowledge can be adapted for the development of new ovarian cancer biomarkers. Further, since mitochondrial dysfunction necessitates the cancer cells reliance on alternate metabolic pathways, we propose targeting these for novel therapeutic interventions of this subgroup of ovarian cancers. In the long term, it is our hope that the knowledge gained from the present work can be adapted to the clinic for the identification and treatment of this unique group of highly chemoresistant ovarian cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610117
Entities
People
- Nadine Hempel
Organizations
- Penn State Milton S. Hershey Medical Center
- United States Army