# Leveraging polyamine metabolic stress as a novel therapy for prostate cancer

> **NIH NIH K00** · UNIVERSITY OF PENNSYLVANIA · 2020 · $76,292

## Abstract

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...

## Key facts

- **NIH application ID:** 9988200
- **Project number:** 5K00CA212455-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** HAYLEY AFFRONTI
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $76,292
- **Award type:** 5
- **Project period:** 2018-07-18 → 2020-08-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988200

## Citation

> US National Institutes of Health, RePORTER application 9988200, Leveraging polyamine metabolic stress as a novel therapy for prostate cancer (5K00CA212455-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988200. Licensed CC0.

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