Iron Chelation Therapy for Ovarian Cancer: Reprogramming the Tumor Microenvironment and the Host Microbiome to Control Disease Progression
Abstract
Standard treatments based on surgery and chemotherapy demonstrate limited success in ovarian cancer, and the 5-year survival rate for patients with metastatic disease remains lower than 27%. It is estimated that ovarian cancer will claim more than 14,000 deaths in the United States in 2019. Thus, new and more effective therapies are urgently needed. Harnessing the immune system to eliminate tumors, termed immunotherapy, is an attractive approach to complement conventional cancer treatments. Immunotherapy has benefited patients with certain types of cancer, including melanoma and lung carcinoma. Yet, ovarian cancer patients remain refractory to this modality. Identifying, understanding and targeting the key molecular processes that promote ovarian cancer progression and immune escape are vital for developing the next generation of therapies against this malignancy. Iron is a trace element that is critical for diverse cellular processes. Malignant ovarian cancer cells have developed iron-dependent mechanisms that enable them to thrive under adverse conditions and resist the effects of chemotherapy. While it has been postulated that ovarian tumors are “iron-addicted,” experimental therapies based on controlling iron accumulation in ovarian cancer remain unexplored. It is also unknown whether iron overload in the ovarian tumor environment affects the anti-cancer capacity of protective immune cells. The central goal of this project is to test whether Food and Drug Administration (FDA)-approved drugs that control iron overload can be repurposed to control ovarian cancer progression, metastasis, and recurrence. We hypothesize that drugs capable of sequestering iron can be used to sensitize ovarian tumors to chemotherapy while simultaneously enhancing the natural capacity that immune cells have to recognize and eliminate tumors. Our research plan will first determine how iron chelation therapy modulates the pro-tumoral attributes of ovarian cancer cells. Second, we will define whether iron chelation therapy modulates the intestinal microbial composition of the host to alter the natural course of disease. Third, we will test the translational hypothesis that iron chelation therapy promotes immune responses capable of extending host survival in preclinical models of metastatic ovarian cancer. Thus, we will also define whether controlling iron overload can be used to enhance the efficacy of immunotherapy in ovarian cancer. The mechanistic and translational concepts proposed herein have not been postulated to date. Since our project focuses on understanding the anti-ovarian tumor effects of FDA-approved drugs already used in other human pathologies, our findings could have immediate clinical applicability toward eliminating ovarian cancer, thus positively impacting the wellness of thousands of patients and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010191
Entities
People
- Juan R Cubillos-Ruiz
Organizations
- United States Army
- Weill Cornell Medicine