Mechanisms of Glutamine Metabolism in Lethal Prostate Cancer Progression and Resistance to Androgen Signaling Blockade in the Metastatic Bony Microenvironment
Abstract
Scientific Objective and Rationale: We previously showed in laboratory studies using mice that glutamine, a component of protein found in our bodies and a variety of foods, was being used as an energy source by prostate cancer cells to support its growth, transformation into an aggressive form of prostate cancer known as neuroendocrine prostate cancer, and resistance to androgen-targeted therapy, one of the most common classes of therapy used to treat prostate cancer. We propose investigating whether levels of glutamine and 4E-BP1 (a molecule that is involved in glutamine metabolism) in the blood from patients diagnosed with prostate cancer are indicators of more aggressive disease and lack of benefit from androgen-targeted therapy. We also propose that, by blocking a source of glutamine utilization by the tumor cells, we can increase our chances in treating prostate cancer with androgen-targeted therapy and reduce the transformation into a more aggressive form of the disease (neuroendocrine prostate cancer) in humans. We will also investigate whether glutamine is important to the spreading of prostate cancer to the bone, which is the most common site of prostate cancer metastases. Applicability and Contribution to Prostate Cancer Research: Prostate cancer was the second-leading cause of cancer death in U.S. men in 2018. This research study will help us better understand the importance of glutamine in contributing to the development of prostate cancer that is resistant to androgen-targeted therapy, has spread to the bone, or has transformed into the neuroendocrine type, all of which are forms of prostate cancer that are incurable and lethal. Our results could show that blocking glutamine utilization by the tumor cells in conjunction with androgen-targeted therapy can be more effective than current the standard of care with androgen-targeted therapy alone. Our project will have both a short-term and a long-term impact. By measuring levels of glutamine and 4E-BP1 from blood samples previously collected from human prostate cancer patients and determining their ability to indicate aggressive prostate cancer and benefit from androgen targeted therapy, we can present a new and convenient blood test that can be used by healthcare practitioners in identifying prostate cancer patients with poorer prognosis. The short-term impact of our findings may also allow us to better identify prostate cancer patients who are more likely to respond to androgen-targeted therapy. These tests may also inform healthcare providers in using additional strategies to effectively treat prostate cancer patients with poorer prognosis who are not likely to respond to androgen-targeted therapy. The next step of our project will be to investigate the drug that blocks the production of glutamine in mice in prostate cancer patients who are resistant to androgen-targeted therapy. The ability to reverse this resistance in mice experiments will lead us to combine androgen-targeted therapy with an inhibitor of glutamine production to enhance the benefit from both drugs. Blocking glutamine utilization may also be useful in treating patients with prostate cancer that has spread to the bone. This goal comprises the long-term impact of our study, and we anticipate that it will take 4 years to finish the mice experiments and guide potential investigation in human prostate cancer patients. Aside from the benefits of this new treatment strategy, the risks of using this treatment include side effects to patients taking this new drug. Investigator Goals and Mentorship: The goal of the Principal Investigator (PI) is to become a clinician-scientist focused on developing more effective therapies and tests that can predict prognosis or benefit to therapies in prostate cancer patients. The PI will be mentored by leading experts in prostate cancer research who have previously trained more than 30 investigators who have developed into independent and suc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910406
Entities
People
- Jun Gong
Organizations
- Cedars-Sinai Medical Center
- United States Army