Abstract
Prostate cancer (PCa) is the most common malignancy among Western men and the second leading-cause of cancer related deaths. For men who develop metastatic castration resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. Using immunohistochemistry we have found that the CPT1A isoform is abundant in PCa compared to benign tissue (n=39, p<0.001) especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased androgen receptor (AR) action and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of these findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust growth inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second highest contributor to cancer deaths in men in the Western World [1]
In order to examine the levels of CPT1A expression in human PCa we evaluated 39 cancer prostatectomy cases from University of Colorado Hospital, Figure 1
These results are in agreement with the database from OncomineTM as shown in Supplementary Table 1 and Figure 1D, where increased expression of CPT1A was observed in high-grade PCa [24]
Summary
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second highest contributor to cancer deaths in men in the Western World [1]. New Highly-Effective Androgen Therapy (HEAT) such as the androgen receptor inhibitor Enzalutamide [6] and the androgen biosynthesis inhibitor Abiraterone acetate [7] have been shown to provide a survival advantage in mCRPC, virtually all patients acquire secondary resistance [8]. In some cases, this is likely mediated by AR variants that promote androgen-regulated programs [9], which affects the lipid metabolic program [10]. AR variant-7 (ARv7) has been identified as the most relevant in insensitivity to HEAT in men with advanced PCa [8]
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