Multimodal Treatment Consisting of Ferroptotic Agent and Chimeric TRAIL as a Second-Line Therapy for Ovarian Peritoneal Carcinomatosis
Abstract
Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Approximately 193,000 patients are afflicted with ovarian cancer at any time in the United States. Five-year survival by ovarian cancer depends on the stage and is 15-20% in third stage and only 5% in fourth stage. Most of these patients die with cancer that has spread to the lining surfaces of the peritoneal (abdominal) cavity. Ovarian peritoneal carcinomatosis (OPC) is a very common ovarian cancer and has historically been considered a terminal condition with merely palliative treatment for achieving pain relief rather than cancer therapy. Over the past 2 decades, our institute and others have introduced extensive cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) as a novel treatment. Although CRS with HIPEC has become the treatment of choice for resectable OPC and has improved the survival of these patients, complete responses have been rare, and recurrences are common due to remained residual microscopic disease. Thus, we need to develop a novel second-line therapy to improve the efficacy of current OPC therapy. Several studies have revealed that the death protein TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces death in a wide variety of tumor cells but does not cause toxicity to most normal cells. Treating OPC with TRAIL holds great promise, but the treatment will not be simple: the likely agent to treat the disease, recombinant TRAIL, does not last long enough in the body to be effective (i.e., it is rapidly excreted in urine). To overcome this limitation, we propose developing a therapy for OPC that utilizes TRAIL fused to part of a protein called immunoglobulin Fc (Fc-TRAIL). The Fc-TRAIL fusion protein displays higher specific activity in vitro, efficient therapeutic activity in vivo, and a significantly longer plasma half-life than unmodified TRAIL and does not exhibit liver toxicity. Since its discovery in 2012, ferroptosis has sparked growing interest in oncology due to its non-apoptotic forms of cell death, which may facilitate the selective elimination of some tumor cells. Previous studies have shown that the antimalarial drug artemisinin and its derivatives, rheumatoid arthritis drug sulfasalazine, and kinase inhibitor sorafenib have anticancer functions. Recently, we reported that a combinatorial treatment consisting of the Food and Drug Administration-approved antimalarial drug artesunate and TRAIL synergistically induces cytotoxicity and effectively enhances tumoricidal efficacy. In this grant application, we hypothesize that a combinatorial treatment of apoptotic agent Fc-TRAIL and ferroptotic agent artesunate can be utilized as a novel therapy to control residual microscopic disease of OPC. We believe that the successful outcome of this study will support the application of this multimodal approach as a second-line therapy to ovarian peritoneal metastases. The application of the combinatorial treatment will impact the health and well-being of Service members, retirees, Veterans, their families, and all women impacted by this terminal disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010190
Entities
People
- Yong Lee
Organizations
- United States Army
- University of Pittsburgh