Dr. Dominic Smiraglia

Metabolic Pathway Can Be Effectively Targeted to Treat Prostate Cancer, Roswell Park Team Shows

Two-drug combination effective in lab studies against aggressive prostate tumors

  • Research team identifies new approach to treating prostate cancer
  • Metabolic targeting effective in lab study against aggressive prostate tumors
  • Combining new, traditional approaches may prevent cancer recurrence

BUFFALO, N.Y. — A Roswell Park Comprehensive Cancer Center research team has identified a novel combination therapy that demonstrates a new approach to treating prostate cancer, reporting their findings in the journal Nature Communications. This new therapeutic strategy is the first to target metabolic processes uniquely important to prostate cancer — specifically, two enzymes in the connected polyamine catabolic pathway and the methionine salvage pathway. 

Dominic Smiraglia, PhD, Associate Professor of Oncology in the Department of Cancer Genetics and Genomics at Roswell Park, led the team that identified this new strategy for treating castration-recurrent prostate cancer, a highly aggressive and therapy-resistant form of the disease.

“The primary problem with prostate cancer therapy is that nearly all men recur after an initial response to androgen deprivation therapy, leaving patients and clinicians with no more good options,” says Dr. Smiraglia. “This new metabolic approach is completely independent of androgen-deprivation therapy. Ultimately, the hope is that it will prevent recurrence during traditional androgen deprivation.”

The new approach is a two-part strategy involving inhibition of the rate-limiting enzyme methylthioadenosine phosphorylase (MTAP) with simultaneous upregulation of spermidine/spermine N1-acetyltransferase (SSAT). The research team hit upon this strategy after observing prostate cancer’s high rate of flux through the polyamine biosynthetic and catabolic pathways. The new treatment takes advantage of the prostate’s innate function of generating and secreting polyamines, key components in human reproduction.

“The prostate makes the highest amount of polyamines of any tissue, and this increases with prostate cancer,” Dr. Smiraglia notes. “This unique but normal state means metabolism of the prostate is uniquely tuned.”

The Smiraglia lab in 2019 developed a new bioinformatics-based approach to monitoring changes in cancer cells, which it employed in the current study. The lab’s previous studies showed that prostate cells are hypersensitive to changes in metabolism that relate to polyamines, resulting in loss of cell growth. The team imagined the engine of metabolism in the cell driving the clinical problems of cancer therapy resistance and metastasis.

In laboratory studies using cancer cell lines, the team then used one drug to force the prostate cancer cells to make even more polyamines, creating metabolic stress, while using a second drug to inhibit a stress-relief pathway to recycle metabolic resources needed to make polyamines.

“Metabolic stress-relief pathways are the oil that lubricates the engine, resolving stress and allowing smooth functioning,” says Dr. Smiraglia. “If we rev the engine by up-regulating polyamine metabolism with one drug, while at the same time blocking the oil needed to lubricate the engine with a second agent, perhaps we can seize the engine, thereby preventing therapy resistance and metastasis. This is a conceptually different approach from the more typical strategy of removing the fuel from the engine.  When those strategies have been tried, the cancer becomes adept at finding new fuels to use.”

The novel combination was able to block cancer growth in prostate cancers, including castration-recurrent prostate cancer, he says, and “offers a potentially fruitful alternate therapeutic direction.”

Prostate cancer remains the leading cause of cancer-related incidence and the third-most-common cause of cancer-related mortality in men in the United States.

These findings were recently highlighted in an article from Science Translational Medicine.

This work was supported in part by several grants from the National Cancer Institute, or NCI (project nos. R01CA197996; CA21245501; R01CA204345, R01CA235863 and P30CA016056, Roswell Park’s Core Grant from the NCI). 


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