Targeting Cholesterol Metabolism in Platinum-Resistant Ovarian Cancer
Abstract
Central Problem: Ovarian cancer tends to come back after surgery and standard chemotherapy. The recurrent tumors are generally resistant to further chemotherapy, particularly to platinum, which is typically the backbone of treatment. Thus, to improve the outcomes of women afflicted with this deadly cancer, studies to understand the causes of resistance to chemotherapy and to develop new treatments are very much needed. Rationale: We have recently discovered a new pathway that allows ovarian cancer cells and tumors to survive and resist eradication by chemotherapy. This pathway is governed by a protective protein called GPX4. We observed that blocking or lowering the levels of GPX4 by using biochemical tools induces cancer cell death and eradicates tumors. However, drugs that directly attack GPX4 are too toxic for use in the clinic. In this project, we propose to study how GPX4 protects resistant ovarian cancer cells and tumors from death induced by chemotherapy and how we can block its actions so that resistant tumors could be eliminated. An early clue is that resistant cancer cells protected by GPX4 have a voracious appetite for cholesterol and rely on it as a source of energy to protect them from chemotherapy-induced death. This makes us reason that, by starving resistant cancer cells from cholesterol intake, we could lower their defense mechanisms and kill them. We engineered a new weapon using a cholesterol disguise around a gold particle called HDL-NP that blocks the main receptor allowing cholesterol intake into cancer cells. We show that this weapon indirectly affects the protective protein GPX4 and eventually drives resistant cancer cells to death. Importantly, this weapon is not toxic to normal tissue and could be developed further for use in the clinic. Research Objectives: Armed with this knowledge, we propose to figure out: (1) how the protective protein GPX4 is linked to the cancer cells’ increased need for cholesterol, (2) how the new weapon HDL NP affects resistant cancer cells grown in laboratory dishes; and 3) how the new weapon HDL NP affects tumors resistant to carboplatin grown in research mice. If our project is successful, we can further develop the new weapon HDL NP for clinical use. Furthermore, we can start other directions of research looking at new ways of blocking cholesterol to attack and eliminate resistant cancer cells. Relevance of the Research Project to the Mission of the OCRP: This research project is directly applicable to women with ovarian cancer and the proposed treatment can make a difference in their battle with this fatal illness. Thus, the proposal fits the mission of OCRP to “support patient-centered research to treat and cure ovarian cancer.” New Paradigms in Ovarian Cancer: This research project proposes a new treatment for women with chemotherapy-resistant ovarian cancer that aims to block the tumors’ defense mechanisms centered around unique sources of energy (e.g., cholesterol) to which resistant cancer cells are addicted. The new therapy could help women who have failed standard chemotherapy and have limited options to extend their lives, therefore addressing a key unmet need in ovarian cancer. Research aiming to improve the outcome of fatal diseases affecting women, such as ovarian cancer, is also of particular significance to the military beneficiaries because the number of women in the U.S. Armed Forces has increased substantially from 2% in 1973 to 15% in 2002. In 2004, of 485,500 active Soldiers, 71,400 were women. Therefore, this translational project is highly significant to Service Members and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110378
Entities
People
- Daniela E. Matei
Organizations
- Northwestern University
- United States Army