Overcoming Chemoresistance in Ovarian Cancer by Targeting a Novel Lipid Hydroperoxidase Pathway
Abstract
Advanced ovarian cancer is, overwhelmingly, an incurable disease characterized by vicious cycles of recurrent chemoresistant and later lethal chemorefractory disease. This disease course points to the existence of a subset of cancer cells that repeatedly fail to die in response to chemotherapy and subsequently give rise to recurrent disease. Most ovarian cancer cells respond to the damage inflicted by chemotherapy by triggering a form of cell suicide known as apoptosis. It has recently emerged that those cells that don t die in response to chemotherapy have activated cellular programs that dismantle their apoptosis machinery. This molecular understanding has clarified that increasing doses of or more frequent administration of chemotherapy are unlikely to have added benefit in cells that cannot trigger the necessary death signals in response to chemotherapy. Instead, most current approaches to address this challenge have centered on the identification of strategies to coax chemoresistant cells to once again re-engage their apoptotic machinery and recover their ability to die. In this proposal, we propose a radically different hypothesis -- that cells that are incapable of undergoing apoptotic death can be killed by instructing them to trigger non-apoptotic forms of cell suicide. In particular, we have recently discovered that therapy-resistant cells across a diverse range of cancer contexts are selectively susceptible to a non-apoptotic form of cell death known as ferroptosis. Ferroptosis results from the buildup of reactive lipid peroxides that are byproducts of the metabolism of cells that exist in a therapy-resistant state. Under normal conditions, a protein known as GPX4 acts to rapidly detoxify these reactive lipids and guard against ferroptosis. Inhibition of GPX4 in these cells causes rapid accumulation of lipid peroxides and ferroptotic death. Importantly, most non-cancer cells generate very few lipid peroxides and are largely impervious to GPX4 inhibition. Through the OCRP Pilot Award, we seek to further explore the potential of GPX4 inhibitors to kill chemoresistant ovarian cancer cells by using clinically relevant patient-derived cells, in vivo models of ovarian cancer. and by generating large-scale data sets that may explain why the lipid metabolism of chemoresistant cells causes this unique susceptibility to ferroptotic cell death. If successful, this work will point to an entirely novel paradigm for how to not just treat ovarian cancer, but cure it. Specifically, the rational combination of GPX4 inhibitors with standard-of-care chemotherapy will represent a therapeutic strategy to achieve complete tumor cell killing in the primary treatment setting, thereby preventing the subsequent emergence of chemoresistant disease. The focus of this proposal on curing ovarian cancer by understanding and addressing treatment resistance makes this proposal highly responsive to the "treatment resistance" FY17 OCRP Area of Encouragement. This proposal focuses specifically on high-grade serous carcinoma (HGSOC), the most common form of epithelial ovarian cancer. However, there are striking similarities between the HGSOC chemoresistant cells we propose to study and the clear cell subtype of ovarian carcinoma in terms of their metabolism and therapy resistance. This raises the possibility that therapeutic insights derived from the work proposed here may have additional relevance for the treatment of clear cell ovarian cancer. The translation aspirations outlined here are timely, given recent successes in our group to generate the first in vivo-active GPX4 inhibitor. A tool compound derived from these efforts, BRD-1331, will be validated in patient-derived xenograft models of ovarian cancer as part of this proposal. An undisclosed clinical lead series is under development with a pharmaceutical partner and will be made available for any future clinical investigation. Active research that is underway outside of this prop
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810809
Entities
People
- Vasanthi Viswanathan
Organizations
- Broad Institute
- United States Army