Leveraging the metabolic stress of polyamine biosynthesis in prostate cancer towards a novel therapeutic approach.

Abstract Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen. This distinctive characteristic places added strain on connected pathways, forcing increased metabolite production from both one-carbon metabolism and the methionine cycle to maintain nucleotide and S-adenosylmethionine (SAM) pools, respectively. More importantly, this stress is increased in prostate cancer (CaP) due to increased polyamine biosynthesis, DNA synthesis, and proliferation. The metabolic flux is driven by the activity of spermidine/spermine N1-acetyltransferase (SSAT), which acetylates the polyamines leading to their secretion into the lumen, which drives demand for biosynthesis of polyamines. To overcome this stress, the methionine salvage pathway (MSP) recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of SAM pools. The rate-limiting enzyme involved in this process is methylthioadenosine phosphorylase (MTAP). We have found that CaP relies on the MSP to relieve the strain caused by high polyamine biosynthesis and that both genetic and pharmacologic inhibition of MTAP blocks CaP xenograft growth. We hypothesized that this dependence can be enhanced by increasing the activity of SSAT. Recent results from our lab have shown that pharmacologic inhibition of MTAP alongside SSAT upregulation is synergistic in multiple androgen-sensitive and castration-recurrent CaP cell lines. We are currently exploring the effects of our combination treatment in castration-recurrent xenografts in vivo as well as in human CaP treatment-naïve tumors from radical prostatectomies grown as ex vivo explants. Preliminary results reveal that our treatments are effective at slowing growth in a subset of xenografts in vivo as well as impacting our target enzymes, polyamine levels, and increasing apoptosis in our ex vivo system. We expect that simultaneous targeting of multiple, converging pathways that are exceptionally important for prostate will lead to significant delay or prevention of disease recurrence. Citation Format: Hayley C. Affronti, Anthony J. Pellerite, Aryn Rowsam, Spencer R. Rosario, Robert A. Casero, Mikhail A. Nikiforov, James Phillips, Dominic J. Smiraglia. Leveraging the metabolic stress of polyamine biosynthesis in prostate cancer towards a novel therapeutic approach [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B052.