Targeting Glutamine Utilization in Therapy-Resistant Prostate Cancer
Abstract
Prostate cancer (PCa) is a hormonal-regulated malignant tumor type that leads to thousands of deaths annually in the United States. Hormonal therapy, which either inhibits androgen synthesis or blocks androgen receptor functions, can initially suppress tumor growth. However, the disease will eventually recur, developing into a hormone-independent stage. Patients with this advanced tumor have limited treatment of choices and the efficacy is rather poor. Therefore, identifying the vulnerability of therapy-resistant PCa raises possibilities to explore novel therapeutic management to ideally compensate the currently applied hormonal therapy. The reprogrammed cellular metabolism has been emerged as one of the most significant cancer hallmarks, and targeting metabolism has become an important therapeutic strategy for many tumors. Our extensive groundwork has firmly demonstrated that, instead of androgen, glutamine becomes the most critical nutrient for the survival and proliferation of hormone-indifferent PCa, suggesting that inhibition of glutamine utilization might be a promising way to treat this lethal disease. The fact that glutamine contains not only carbon, but also nitrogen atoms, enables glutamine as a pleiotropic factor in cellular metabolism. Interestingly, both glutamine carbon and nitrogen metabolism are highly enhanced in therapy-resistant PCa, which maintain the tricarboxylic acid (TCA) cycle activity and increase pyrimidine nucleotide biosynthesis, respectively. To maximally starve tumor cells by diminishing glutamine usage suggests that both glutamine carbon and nitrogen pathways need to be inhibited. Targeting the rate-limited enzymes is the best approach to slowing down metabolic rates. Our previous metabolomics and bioinformatics analyses reveal that glutaminase 1 (GLS1) and carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are the key enzymes responsible for glutamine carbon catabolism and glutamine-derived pyrimidine anabolism, respectively. As anticipated, suppressing GLS1 enzymatic activity by applying the selective inhibitor, CB-839, attenuates tumor growth. However, the efficacy is moderate, suggesting that monotherapy is not sufficient. Based on these background, rationale, and preliminary findings, in the current application, we will further determine the role of CAD about how it affects the biological behavior of advanced PCa through mediating glutamine nitrogen metabolism. We will also test a potentially combinatorial therapeutic approach to completely targeting glutamine utilization of therapy-resistant PCa by inhibiting glutamine carbon and nitrogen metabolism simultaneously. With the success of this proposal, we believe that the new synergistic treatment option will definitely benefit those advanced PCa patients who have developed hormonal therapy-resistance. I have been fortunate enough to work at Dr. Jiaoti Huang’s laboratory in Duke University as a postdoctoral associate since July 2019. My career goal is to become an independent investigator in an academic institution and find a cure for PCa. I will achieve my goal by studying the molecular mechanisms, especially cellular metabolism of PCa, and translating findings to benefit patients. Should this application be approved, it would further my scientific work as well as strengthen my training as a comprehensive PCa biologist. I will actively participate in various workshops, especially in genomic technologies, computational approaches, and mass spectrometry analyses, to expand my expertise in areas essential to my ongoing and future research. I will also present my data at regional, national, and international conferences. This award will provide me an opportunity to publish my results in high-impact journals, which would in turn help with my future funding applications. Additionally, I have an amazing mentor team. Drs. Jiaoti Huang (primary mentor) and Daniel George (co-mentor)
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110034
Entities
People
- Lingfan Xu
Organizations
- Duke University
- United States Army