The most common treatment options for prostate cancer (CaP) patients initially presenting with localized disease are surgery and radiation. However, both approaches can result in significant side-effects, which impact quality of life. Furthermore, some patients present with comorbidities that make these approaches unviable options. A low-risk, low-morbidity therapy would provide an important new alternative. My thesis project studies the prospects of using novel treatments as an alternative option for patients presenting with localized CaP by taking advantage of inherent metabolic strain in prostate cells due to their extraordinary level of polyamine biosynthesis. Recent findings have shown that the high levels of polyamine biosynthesis, which consumes S-adenosylmethionine (SAM) pools, puts enormous demands on one-carbon metabolism and the methionine cycle to maintain nucleotide and SAM pools. This state of extraordinary levels of polyamine biosynthesis is enhanced in CaP. The system is driven by the activity of spermidine/spermine N1- acetyltransferase (SSAT), which acetylates the polyamines leading to their secretion into the lumen, requiring cells to synthesize polyamines to maintain intracellular levels. 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), and our preliminary findings strongly suggest that this pathway is a major player in homeostatic regulation of metabolite pools in CaP cells given their high level of flux through the polyamine biosynthetic pathway. Our central hypothesis is that the MSP is critical to CaP due to high metabolic flux through polyamine biosynthesis, and that this dependence can be enhanced by increasing the activity of SSAT. Therefore, targeting these pathways may provide novel therapeutic strategies to treat localized CaP. Additionally, this approach leverages a prostate specific stress, providing a therapeutic window in which the CaP, and perhaps prostate tissue, can be strongly affected with limited toxicity to other tissues in comparison to standard treatment. This hypothesis has been tested previously in vitro (discussed in Aim 1) with future work underway to test this hypothesis in vivo (discussed in Aim 2). We propose that by combining polyamine catabolism upregulation (to increase metabolic stress) and MSP inhibition (to prevent mitigation of that stress) will lead to crisis and apoptosis in CaP cells. We expect that simultaneous targeting of multiple, converging pathways that are exceptionally important for prostate will provide a new therapeutic option for patients with localized CaP. Our long term goal is to take advantage of this in a clinical setting to provide an alternative therapy for patients with localized CaP. Additionally, this project lays the foundation for pursuing a postdoctoral position (discussed in Aim 3) with a principal investigator well-versed in leveraging metabolic stresses to develop cancer therapies as I strive to become a highly productive independent investigator.
Cancer of the prostate is the most commonly diagnosed non-cutaneous cancer in American men; for patients presenting with localized prostate cancer requiring treatment, only a small number of options exist and therefore a low-risk, low morbidity therapeutic option would be an important new option for these patients. Our proposed therapeutic approach will test novel combination therapies intended to provide an alternative therapy for patients presenting with localized prostate cancer by taking advantage of a metabolic strain in prostate cells and accentuating that strain while also blocking a metabolic pathway that would normally alleviate the strain. If successful, this research will open up novel alternative therapeutic strategies for men presenting with localized prostate cancer and will provide me with an excellent foundation for pursuing a postdoctoral opportunity as I strive to reach my future goal of becoming an independent investigator.
| Rosario, S R; Long, M D; Affronti, H C et al. (2018) Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas. Nat Commun 9:5330 |
| Affronti, Hayley C; Long, Mark D; Rosario, Spencer R et al. (2017) Dietary folate levels alter the kinetics and molecular mechanism of prostate cancer recurrence in the CWR22 model. Oncotarget 8:103758-103774 |
| Bianchi-Smiraglia, Anna; Rana, Mitra S; Foley, Colleen E et al. (2017) Internally ratiometric fluorescent sensors for evaluation of intracellular GTP levels and distribution. Nat Methods 14:1003-1009 |
