National Cancer Institute 11382089

Modulation of intracellular lipid access by ATGL determines ferroptosis sensitivity in castration-resistant prostate cancer

This award funds research on the role of adipose triglyceride lipase (ATGL) in castration-resistant prostate cancer (CRPC) and its impact on sensitivity to ferroptosis, a form of cell death. The project aims to understand the biology behind ATGL's role, test combination therapies involving ATGL inhibition and ferroptosis inducers, and identify biomarkers to guide treatment, potentially leading to new effective therapies for lethal prostate cancer.

Description

Existing therapies for advanced prostate cancer, including androgen deprivation therapy and chemotherapy, remain insufficient once patients acquire resistance, thus resulting in unsatisfactory long-term survival outcomes for patients harboring aggressive or metastatic disease. By identifying a key enzyme involved in lipid metabolism, known as adipose triglyceride lipase (ATGL), that engenders metastatic castration-resistant prostate cancer with the ability to resist ferroptotic cell death, this F99/K00 proposal aims to 1) determine the underlying biology driving the synergy between ATGL inhibition and ferroptosis inducers—an emerging class of remarkably potent cancer therapeutics, 2) examine the safety and efficacy of novel ATGL-directed combination therapies, and 3) identify potential biomarkers of ATGL and ferroptosis that could guide future therapeutic applications. The success of this proposal could pave the way for novel treatment regimens that are highly effective in patients with lethal prostate cancer, thus improving the quality of life for prostate cancer survivors.

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