By Deborah Borfitz 

November 18, 2021 | Evidence has been mounting for decades that what men eat can lower or raise their risk of prostate cancer—including aggressive forms of the disease that can be lethal. But that’s only part of the story, according to Nima Sharifi, M.D., director of the Center for Genitourinary Malignancies Research at the Cleveland Clinic’s Lerner Research Institute. 

Other considerations are how the gut acts on food taken in and the role of nutrients and gut microbial metabolites in the body, he says. Many disease-associated risk factors other than diet have also been identified, including advancing age, African American ethnicity, and family history. 

The reason prostate cancer happens in the first place remains a mystery. It is likewise unknown why some men develop metastatic disease and are lucky to live five years beyond their diagnosis despite medical therapy or surgical intervention while many others get the indolent type and live symptom-free for years under active surveillance. 

Sharifi and his Cleveland Clinic colleagues wanted to know the risk factors for developing the deadly form of prostate cancer. Their study, which recently published online in Cancer Epidemiology, Biomarkers & Prevention (DOI: 10.1158/1055-9965.EPI-21-0766), implicated elevated levels of a metabolite called phenylacetylglutamine (PAGln) and the nutrients choline and betaine.  

The link with the nutrients, abundant in meat and dairy products, solidified findings of previous studies, he says. But the association with PAGIn was a surprise because it involves both the intake of phenylalanine, an amino acid found in many plant- and animal-based protein sources, and gut microbial metabolism breaking it down to form the culprit metabolite. 

Among a cohort of nearly 700 men who donated blood samples two decades ago as participants in the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, those with high PAGIn were two to three times more likely to later be diagnosed with lethal prostate cancer. The comparison groups were those who perished from the disease (173) and all others, including 519 non-lethal cases of prostate cancer or no prostate cancer. 

Common Foe? 

PAGIn was previously associated with increased cardiovascular risk by another researcher on the study, Stanley Hazen, M.D., Ph.D., director of Cleveland Clinic’s Center for Microbiome & Human Health. The metabolite binds to the same adrenergic receptors as beta blockers, suggesting their effectiveness may be in part a result of blocking PAGIn’s activity, as reported last year in Cell (DOI: 10.1016/j.cell.2020.02.016). 

Additionally, “insights are emerging from large-scale clinical datasets that show use of beta blockers is also associated with lower mortality due to prostate cancer,” Sharifi says. Cleveland Clinic researchers will therefore continue investigating the possible mechanisms linking PAGln to prostate cancer disease processes in hopes of identifying new therapeutic targets for patients. 

Physicians will generally tell men that eating a heart-healthy diet will probably also benefit their prostate, says Sharifi. Studies conducted years ago on male populations who migrated out of East Asia implicated the Western diet—containing high amounts of processed foods, red meat, high-fat dairy products, high-sugar foods, and pre-packaged foods—in higher incidences of prostate cancer.  

Cardiovascular and prostate health now appear to have found a common foe with PAGIn. “If this is truly what drives the development of lethal prostate cancer, or a component of it, then that is something that can be blocked,” Sharifi says. 

With the latest study, investigators were concerned with men’s risk of developing aggressive prostate cancer rather than its treatment or potential as a disease biomarker. It took seven years to go from conception to completion, he notes. 

Therapeutic Avenues 

Sharifi and his colleagues are now looking at other aspects of metabolism that could influence the effectiveness of prostate cancer treatments, such as hormonal therapy, he adds. How certain bacteria in the gut microbiome may be linked to the efficacy of systemic therapies in cancer, such as immune therapies for people with metastatic disease, is another active area of ongoing research. 

Life science companies focused on prostate cancer are mainly working on pharmacologic treatments for men who have advanced disease, says Sharifi. In oncology in general, there is also considerable interest in understanding the genetic drivers of tumors in individual patients to inform treatment choices. 

One intriguing possibility specific to PAGIn is that the metabolite may somehow be related to prostate cancers that invade the nerves, says Sharifi. It has been observed that neural invasion often means prostate cancer is more aggressive and perhaps it is because those tumors are intrinsically different than others originating in the prostate. The theory is backed by the fact that PAGIn works through adrenergic receptors that tie into the nervous system. 

If true, PAGIn might be a therapeutic target to either suppress the activity of an otherwise fast-growing tumor or the risk of getting aggressive prostate cancer in the first place, he says. “It’s hard to say right now.”  

Dietary recommendations will always be in the mix since, directly or indirectly, they’re the source of all metabolites. But, as Sharifi well knows, it can be “very difficult to make consistent dietary changes over time and to keep them.” 

Research in this arena is not going nearly as fast as anyone would like, says Sharifi, but with more sustained support “progress certainly is coming … both [for] people who are at risk for developing prostate cancer as well as men who eventually get [it].”