The Role of Polyamine Metabolism in Advanced Prostate Cancer
Abstract
Research Objectives and Potential to Help Patients: The goal of our research is to develop innovative and effective therapies to prolong the lives of patients with advanced prostate cancer. Currently available therapies are only effective for a limited duration of time due to the cancer developing resistance. Moreover, current therapies for prostate cancer have failed to recruit the assistance of the body’s immune system to help fight the cancer. We believe that the metabolism of prostate cancer, i.e., the way that nutrients are processed and utilized, becomes programmed to promote resistance to therapy and silencing of the immune system. Specifically, our preliminary data suggest that the central driver of prostate cancer, the androgen receptor, stimulates the production of polyamines. These polyamines function to promote cancer cell resilience under the stress of therapy and are potently immunosuppressive. Using prostate cancer models, we observed greater death of prostate cancer cells when polyamine synthesis is inhibited by a drug called difluoromethylornithine (DFMO) in combination with other therapies. On this basis of these data, we are opening a clinical trial targeting the androgen receptor in combination with DFMO for patients with advanced prostate cancer. DFMO is an approved medicine for a parasite infection called trypanosomiasis and has very few side effects. The overall goal of this proposal is to define how polyamine metabolism regulates prostate cancer cell fate and evasion of the immune system following hormonal therapies. We will study patient biopsy samples obtained from our clinical trial to validate mechanistic work using prostate cancer models. These studies will enable rational development of novel therapeutic strategies that overcome resistance and immunosuppression for patients with lethal prostate cancer. Career Development and Training of the Candidate: Laura Sena is the candidate principal investigator for this award. She is currently a medical oncologist at Johns Hopkins University who cares exclusively for patients with advanced prostate cancer. She has a Ph.D. in molecular biology and cellular metabolism. She completed internal medicine and oncology subspecialty training at Johns Hopkins Hospital and became a faculty member in October 2021. Her career goal is to develop better therapies for patients with prostate cancer to improve their duration and quality of life by targeting cellular metabolism. This proposal includes a career development training plan with dedicated mentorship, a scientific advisory committee, didactic and hands-on research, and interaction with the wider prostate cancer community to provide Dr. Sena with skills and experience to become a leader in this field. Her mentors for this award are Samuel Denmeade and Robert Casero. Dr. Denmeade is the director of GU medical oncology at Johns Hopkins, is a world-renowned translational prostate cancer researcher, and will serve as Dr. Sena’s clinical/translational mentor with specialty in prostate cancer. Dr. Casero is a molecular biologist with extensive expertise in polyamine metabolism in cancer and other disease settings and will serve as Dr. Sena’s laboratory mentor with specialty in polyamine metabolism. Overall, this project will integrate two distinct areas of expertise by these mentors, provide numerous training opportunities for Dr. Sena, and drive a new line of investigation that has significant potential to help patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310107
Entities
People
- Laura Sena
Organizations
- Johns Hopkins University
- United States Army