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2024 The John & Daria Barry Foundation – PCF Young Investigator Award

Targeting Metabolic Rewiring to Inhibit Castration-Resistant Prostate Cancer Progression and Bone Metastasis

Estefania Labanca, PhD
The University of Texas MD Anderson Cancer Center

Mentors: Chris Logothetis, MD; Daniel Frigo, PhD; Geraldine Gueron, PhD

Description:

  • In patients with metastatic prostate cancer, resistance to androgen deprivation therapy (ADT) and progression to castrate-resistant prostate cancer (CRPC) remain mostly inevitable. Bone metastases are the dominant site of metastasis for prostate cancer, and manifest the treatment-refractory lethal phenotype. The mechanisms that drive metastasis to bone remain unclear, but may involve metabolic alterations that enable the energetic reprogramming needed for adaptation to the bone environment. 
  • Dr. Estefania Labanca’s project will investigate the role of altered metabolism in treatment-resistant prostate cancer and novel treatment options to inhibit progression to lethal bone metastases. Her prior studies identified the metabolism of ketone bodies, which can be utilized as an alternative energy source, as associated with CRPC and reduced overall survival in patients with bone-metastatic prostate cancer. 
  • This project will characterize the metabolic profiles of different clinical states of prostate cancer to determine alterations in CRPC and prostate cancer bone metastases. 
  • The therapeutic efficacy of inhibiting ACAT1, a key enzyme in ketone body metabolism, will be investigated in prostate cancer models. The mechanism of action of ACAT1-inihbitors, including impact on tumor growth and metabolic processes, will be determined. The FDA-approved ACAT1 inhibitor arecoline hydrobromide will be specifically investigated.
  • If successful, this project will define the roles of ketone body metabolism in the tumor-associated microenvironment in bone and will identify biomarkers of progression, and determine the therapeutic potential of blocking this metabolic pathway for preventing the progression of prostate cancer to lethal disease states.

What this means to patients: Understanding the molecular drivers of prostate cancer treatment resistance and metastasis are key to identifying new treatment strategies. Dr. Labanca’s project will define the role and mechanisms of altered metabolism in enabling prostate cancer metastasis to bone and resistance to androgen blocking therapies, and determine whether blocking ketone metabolism has potential as a new therapeutic strategy. This could lead to new treatments that prevent prostate cancer progression to lethal disease states and improve patient outcomes.