Targeting Glutaminase Isoforms for Therapy-Resistant Prostate Cancer
[Technical Report, Annual Report]
DUKE UNIV DURHAM NC
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Our preliminary study demonstrates that advanced prostate cancer is addicted to glutamine, and a glutaminase isoform switch contributes to the development of therapy resistance and disease progression. The major goal of the project was to study the molecular mechanisms of GLS1 isoform switch and explore the possibility of targeting glutamine metabolism as a novel therapeutic approach. In addition to the achievements reached in Year 1, this year, we have made the following Key Research Accomplishments 1. We have demonstrated a potential mechanism by which AR regulates GLS1 gene expression coupled with its mRNA splicing. 2. We have demonstrated a role of GAC, the more potent isoform of GLS1, for driving therapeutic resistance and disease progression in vitro and in vivo. 3. By establishing KGA-GAC-specific expression cell models, we have demonstrated that GAC displays higher enzymatic activity and its expression leads to more aggressive biological behavior of PCa tumor cells.
- Medicine and Medical Research