Interviews

Dr Labanca Talks Use of Non-Canonical AR Signaling, Ketone Body Fuel in CRPC

Dr Labanca

My name is Estefania Labanca. I am a PhD, postdoctoral fellow, in Dr. Navone's Laboratory, Department of Genitourinary Medical Oncology, at the University of Texas MD Anderson Cancer Center.

I will briefly discuss our study on castration‑resistant prostate cancer (CRPC) progression usage of non‑canonical androgen receptor signaling and ketone body fuel, which was presented at the AACR Annual Meeting this year.

This work was done in close collaboration with an outstanding team led by Dr Gueron at the University of Buenos Aires in Argentina, and we have submitted a manuscript that is currently under revision for publication.

Prostate cancer is the second leading cause of cancer‑related death in men in the United States. Androgen‑signaling inhibition and androgen receptor, or AR‑targeting agents, remain the standard of treatment for advanced disease, despite the emergence of resistance and progression to castrate‑resistant prostate cancer, or CRPC, in most cases.

Thus, there is an urgent need to further understand the mechanisms that account for response and resistance to therapy as we develop effective treatment strategies to improve patient care.

It is known that deregulated oncogenic and/or tumor suppressor pathways affect cancer cell metabolism. In addition, the characteristic hypoxic environment of many tumors force cancer cells to adapt and exploit alternative fuel sources.

However, progress in comprehending the intricate changes in the metabolic program during prostate cancer progression, has been hampered by the lack of models.

Our laboratory is home to one of the largest collections worldwide of prostate cancer patient‑derived xenografts. This is the MDA PCa PDX series, representative of the clinical spectrum and complexity of prostate cancer.

The initial characterization of this cohort that has provided unique insights into the biology of this disease attesting to their clinical relevance of these models was recently published in Clinical Cancer Research.

In this work, we assessed the metabolic changes occurring during CRPC progression in a subpopulation of prostate cancer that progressed with partial or complete loss of AR‑dependence using PDX that mimic human donor response to androgen deprivation therapy.

For the first time, we performed a comprehensive metabolomic analysis of prostate cancer PDX that relapsed following castration. Interestingly, we discovered a metabolic shift from high glycolytic activity to exacerbated ketone body metabolism, indicating that a subset of CRPCs that reduce nuclear AR, increase cytoplasmic AR, and loss of ERG are fueled by ketone bodies.

Ketone bodies are high‑energy mitochondrial fuels that can be converted back into acetyl coenzyme A which is vital for amino acids, ATP, and fatty acid synthesis. Therefore, the ketone bodies can be utilized as an energy source.

We confirmed that expression of critical ketogenic/catalytic enzymes, namely ACAT1, BDH1, and OXCT1 is upregulated, after CRPC progression in both the PDX tumor and the human donor tissue.

We further analyzed expression of these ketogenic/catalytic enzymes in silico in prostate cancer cohorts from public database repositories, where we found increased levels of these enzymes in a subset of prostate cancer patients that relapsed with low AR, and ERG and their expression correlated with biochemical relapse and decreased progression‑free survival.

Our studies, therefore, reveal the key metabolites fueling castration‑resistant progression in a subpopulation that does not use the canonical AR‑signaling during early relapse to androgen deprivation therapy.

These metabolic changes may serve as a foundation to identify early biomarkers of CRPC progression in a larger clinical study in order to harness them for clinical purposes. ACAT1, one of the key enzymes involved in the conversion of ketone bodies into acetyl‑coA, was proposed as a druggable target for cancer therapy.

In this study, we report an increase in ACAT1 in prostate cancer and its association with relapse to androgen deprivation therapy; therefore, supporting ketone body as the main energy source driving CRPC and proposing targeting this enzyme as a promising therapeutic intervention for CRPC.

Our next step is to assess whether blockade of ketone body conversion to acetyl‑coA will delay CRPC progression. Because bone is the primary site of CRPC progression, we will first study the response of clinically relevant PDX growing in the bone of mice to androgen deprivation therapy.

We will then evaluate our findings related to this metabolic shift and the concurrent cellular and biochemical events that occur after androgen deprivation therapy in patients, in prostate cancer biopsy specimens, obtained from different clinical states from the large patients' population that we have available in the institution.

Further, we will use an FDA‑approved ACAT1 inhibitor to test therapeutic utility in our preclinical models and curving CRPC development with putative application in the clinical setting.

This will serve as a proof of principle to further design novel inhibitors of ACAT1 and others critical ketogenic/catalytic enzymes that could delay CRPC progression. Therefore, our studies will help pinpoint a therapeutic window for early intervention in prostate cancer.

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