Ketone Bodies as the main metabolic fuel driving Castrate-Resistant Prostate Cancer

ESTEFANIA LABANCA; PABLO SANCHIS; VALERIA ANTICO; ANH HOANG; JAVIER COTIGNOLA; ELBA VAZQUEZ; ESTEFANIA LABANCA; PABLO SANCHIS; VALERIA ANTICO; ANH HOANG; JAVIER COTIGNOLA; ELBA VAZQUEZ; JUN YANG; ALEJANDRA PAEZ; SOFIA LAGE VICKERS; ELENI EFSTATHIOU; CHRISTOPHER LOGOTHETIS; GERALDINE GUERON; JUN YANG; ALEJANDRA PAEZ; SOFIA LAGE VICKERS; ELENI EFSTATHIOU; CHRISTOPHER LOGOTHETIS; GERALDINE GUERON; JUAN BIZZOTTO; PETER SHEPERD; NICOLÁS ANSELMINO; MARK TITUS; JOHN ARAUJO; NORA NAVONE; JUAN BIZZOTTO; PETER SHEPERD; NICOLÁS ANSELMINO; MARK TITUS; JOHN ARAUJO; NORA NAVONE

Congreso; Prostate Cancer Foundation Scientific Retreat 2020; 2020

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant PCa, include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. It is well known that oncogenic alterations modify the metabolic program of cancer cells. However, the intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis. In this work using PCa patient-derived xenografts (PDXs) we assessed the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body content compared with baseline (i.e., tumors after castration but before relapse). Importantly, we confirmed that expression of critical ketogenic/ketolytic enzymes (ACAT1, OXCT1, BDH1) were significantly augmented after castrate-resistant progression in the PDX tumor. We discover that these enzymes are increased in the human donor tissue after progressing to ADT, thus providing added relevance to our findings as a mechanism of human PCa progression.In an in silico approach, increased ACAT1 and OXCT1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG expression. Further, high levels of these factors were also associated with decreased biochemical relapse and progression free survival. In summary, our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.