Enhancing Immunotherapy by Triggering Ferroptosis
Abstract
The Critical Problem in Ovarian Cancer Addressed in the Proposed Research: Most women diagnosed with epithelial ovarian cancer enter a period of disease remission following surgical removal of the cancer and chemotherapy. However, this initially promising response is often followed by disease recurrence, frequently months and sometimes years later. The recurrent tumors often show limited response to chemotherapy effective for the primary tumors. Therefore, we urgently need to identify new approaches to target these recurrent tumors to reduce the resulting suffering and death. While immunotherapy has been effective for many tumor types, its efficacy for ovarian cancer has been quite disappointing. Therefore, our proposal will address how to turn the “cold” tumors to “hot” tumors and sensitize ovarian to immunotherapy. We have developed a new model of tumor recurrence by injecting ovarian cancer cells into the abdominal cavity of mice to allow tumors to form in an environment that mimics where these cells occur in human disease. After tumors develop, we treat the mice with carboplatin and paclitaxel, commonly used agents for ovarian cancer that are effective at eliminating most tumor cells. However, the resistant tumor cells eventually form recurrent tumors that are often resistant to chemotherapies. This reflects many aspects of the development of recurrent ovarian cancers in patients. We have found recurrent tumor cell have special need for outside nutrients that may allow us to pre-emptively reduce or eradicate recurrent disease. Just as we require food (sugars or proteins) and oxygen to live, our cells also rely on outside nutrients they must obtain from their environment for their survival. Compared to normal cells, cancer cells often have increased and different demands for nutrients from the surrounding environment, including extracellular amino acid cysteine for survival. The removal of cystine rapidly triggers a special kind of cell death called “ferroptosis” that even resistance cells are still sensitive to. This can be further enhanced by immunotherapy. Importantly, we have found that we can deplete the plasma cysteine in mice using a novel form recombinant cyst(e)inase that have been shown to be safe and have strong anti-tumor effects. This cyst(e)inase is being developed by a drug company for anti-tumor treatments. Therefore, the cyst(e)inase may treat or prevent tumor recurrence and overcome resistance to chemotherapy. Describe How the Proposed Research Is Relevant to the Vision and Mission of the OCRP: Our objective to identify novel treatment strategies to delay or ideally prevent recurrent ovarian cancer is highly relevant to the vision and mission of OCRP to “to support patient-centered research to prevent, detect, treat, and cure ovarian cancer.” What Types of Patients Will It Help and How Will It Help Them? Since most women with ovarian cancer are at risks for recurrent. Our efforts to reduce or possibly even eliminate disease recurrence, thus benefiting the majority of women with advanced epithelial ovarian cancer. What Are the Potential Clinical Applications, Benefits, and Risks? We will identify and validate that in vivo ferroptosis can be used to enhance immunotherapy of OVCA. We will also learn how to predict which tumors will respond to these new treatments. If successful, this will lead to an entirely new regimen of treatment that target how tumor cells develop resistance to chemotherapies. This proposal is based on our dramatic preclinical observations and includes available recombinant cyst(e)inase, under clinical developments, that can effectively starve the tumor cells of cystine. The recombinant cyst(e)inase is current being developed for early clinical development by a drug company. Therefore, depending on the progresses of the drug development and regulatory procedures, they can be available in 3-5 years. Risks of this approach include the possibility of undesir
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110568
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army