Editors' ChoiceCancer

Hitting a double to treat cancer

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Science Translational Medicine  22 Jan 2020:
Vol. 12, Issue 527, eaba2910
DOI: 10.1126/scitranslmed.aba2910

Abstract

Simultaneous targeting of polyamine and methionine pathways may be a promising strategy to treat prostate cancer.

Polyamines are naturally occurring compounds essential for cell proliferation and other vital processes. In normal physiological conditions, polyamine concentrations are tightly regulated by balancing production, degradation, import, and export. Because of their roles in cellular growth, polyamines are highly abundant in many cancers. In the current study, Affronti et al. tested whether enhancing polyamine export to drive a compensatory increase in synthesis would create a metabolic dependency on the methionine salvage pathway, leading to reduced proliferation.

The methionine salvage pathway replenishes methionine and its derivatives which are crucial for the production of a range of cellular nutrients. For example, replenishing S-adenosyl methionine (SAM) enhances the flux of polyamine biosynthesis. Therefore, blocking SAM generation or the methionine salvage pathway could potentially open a therapeutic window to treat cancers with a high polyamine synthetic capacity. To induce the flux of polyamine synthesis, Affronti et al. used the polyamine analog BENSpm which enhances the activity of spermidine/spermine-N1-acetyltransferase (SSAT), an enzyme that acetylates polyamines and enhances their export. Using in vitro experiments, the authors found that BENSpm or its combination with an inhibitor of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme of the methionine salvage pathway, achieved a synergistic antiproliferative response in prostate cancer cell lines. Treatment with BENSpm or the combination were associated with a decrease in polyamines and an increase in intracellular reactive oxygen species depending on the cell line tested.

To test treatment efficacy in vivo, the authors treated established prostate cancer xenografts grown in castrated immunocompromised mice and found that a combination of BENSpm and MTAP inhibitor was more effective at controlling tumor growth compared with each agent alone. To test the relevance to human disease, the authors tested combined treatment in an ex vivo explant system using fresh tissue collected from radical prostatectomies and found that treatment induced apoptosis, increased SSAT expression, and decreased tissue polyamines.

Overall, this investigation is of clinical importance considering that deletion of MTAP is common in many cancers due to its proximity to the locus encoding the tumor suppressor p16. Thus, it is worth testing whether polyamine-targeting approaches are efficacious in this cohort of patients. One caveat of the study is a lack of stable isotope–tracing studies that could reveal distinct patterns of metabolic enzyme activities during treatment. Additionally, because of the emerging role of polyamines in the immune response, investigating the efficacy of this combination in models that possess fully functioning immune system would better reflect human prostate cancer.

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