Leveraging Polyamine Metabolic Stress To Enhance Sensitivity To Epigenetic Therapy For Prostate Cancer.

While polyamines are required for proliferation in all cells, the prostate synthesizes and secretes high levels into its lumen, resulting in depletion of intracellular polyamines. To meet polyamine biosynthetic demands, which is enhanced in Prostate Cancer (CaP), there is high flux through one carbon metabolism to provide S’-Adenosylmethionine (SAM), which donates its aminopropyl group to polyamine synthesis. This flux is driven by Spermidine/ Spermine N1-Acetyltransferase (SSAT) which adds acetyl groups to spermidine and spermine, leading to their secretion. To deal with the stress, the methionine salvage pathway (MSP) recycles one carbon units lost during polyamine synthesis back to the methionine cycle for SAM replenishment, by methylthioadenine phosphorylase (MTAP). We have shown increased polyamine catabolism by SSAT stabilization and MTAP inhibition results in cell death in in vitro, in vivo, and ex vivo CaP models. We expect the CaP epigenome to be impacted by stressed acetyl-CoA and SAM pools, which are used by chromatin modifying enzymes, and that this stress will alter CaP sensitivity to epigenetic based drugs. While epigenetic therapies are currently being investigated in the clinic for targeting CaP, their success has been limited due to toxicity and non-specificity. We hypothesize that increased flux through polyamine metabolism and one carbon metabolism disrupts SAM and acetyl-CoA pool maintenance, making CaP cells sensitized to therapy targeting their utilization. Our findings suggest that certain histone modifications are affected by treatment with BENSpm in vitro. Additionally, we have found treatment of CaP cells with BENSpm and MTDIA induces significant broad DNA methylation changes. Furthermore, our preliminary data shows that the addition of metabolic therapies, BENSpm and MTDIA, to an epigenetic targeting drug, JQ1, further suppresses CaP growth in vitro. We expect that future studies combining our metabolic therapies with epigenetic drugs targeting acetyl-CoA and SAM usage will maintain anti-tumor efficacy with reduced systemic toxicity. Citation Format: Aryn M. Rowsam, Hayley C. Affronti, Spencer R. Rosario, Mark D. Long. Leveraging polyamine metabolic stress to enhance sensitivity to epigenetic therapy for prostate cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-037.