The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy
Abstract
Despite current surgical and cytotoxic therapies, 80% of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and only 30% of patients survive 5 years following diagnosis. My goal is to improve the overall survival of patients suffering from this devastating disease. I became committed to ovarian cancer research during my postdoctoral fellowship at Stanford where I identified and developed a targeted therapy for ovarian cancer based on inhibiting the GAS6/AXL signaling pathway that is upregulated during metastasis. Through my collaborations with gynecologic oncologists, I became aware of the unmet need for effective therapies in the management and treatment of ovarian cancer. Thus, I have directed my research efforts towards identifying and developing therapeutic strategies for the treatment of advanced ovarian cancer. With the development of chemoresistant disease in the majority of ovarian cancer patients, targeted therapies are at the forefront of ovarian cancer therapy. However, ovarian cancer tumors have very few common genomic alterations that are therapeutically druggable. Therefore, the targeted therapies that have achieved the greatest responses in ovarian cancer patients are those that target the tumor microenvironment. Hypoxia, or low oxygen supply, is a common molecular feature of the solid tumor microenvironment. As a tumor progresses, it will outgrow the oxygen supply provided by existing blood vessels. Tumor cells and other cells within the tumor microenvironment then become starved for oxygen and induce a response to turn on the expression of genes that allow them to survive and adapt within the hypoxic environment. The hypoxia inducible transcription factors (HIFs) are the primary molecular mediators of hypoxic responses in both tumor cells and in supporting cells of the tumor microenvironment. Therefore, I hypothesize that hypoxia through HIF signaling in tumor cells and in key supportive cells of the tumor microenvironment, such as regulatory T cells, is responsible for driving the protumorigenic properties of the tumor microenvironment. Importantly, therapeutic inhibition of HIF may be an effective strategy to inhibit ovarian cancer tumor growth and survival. My research focuses on dissecting the role of HIF signaling within the ovarian cancer tumor microenvironment and evaluating the effects of HIF inhibition on ovarian cancer tumor growth, angiogenesis, and immune suppression. Since HIF inhibitors are in early stages of clinical development, these studies will provide the foundation for future clinical trials with these agents in ovarian cancer. We anticipate that HIF inhibitors will be more effective and safer than current chemotherapeutic treatments. Our therapeutic approach is a novel and will be particularly useful for recurrent ovarian cancer patients whose tumors do not respond to current chemotherapy regimes. In summary, these studies will identify novel therapeutic strategies to treat advanced ovarian cancer and will provide the preclinical data to support the design of clinical trials using these agents within the next 5 years. This research meets the specific needs outlined by the Department of Defense to improve the overall survival and quality of life for military Service members, their families, and other military beneficiaries that are either directly or indirectly affected by this devastating disease. Obtaining the Ovarian Cancer Academy Early-Career Investigator Award will significantly contribute to the success of my career. This award supports many of the critical features of my career development plan including extramural funding to support the early phases of my ovarian cancer research, funds to support the utilization of cutting-edge technology for my research, a budget to consult with biostatisticians, funds to attend a course on tumor immunology to support my research project, and funds to travel to meetings that will foster c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510097
Entities
People
- Erinn B. Rankin
Organizations
- Stanford University
- United States Army