Detecting risk of metastatic prostate cancer in Black men

Newswise — SAN FRANCISCO, Aug. 15, 2023 — To explore why prostate cancer disproportionately sickens and kills Black men, researchers are looking to another disorder, diabetes, which alters metabolism. They used this approach in a preliminary clinical trial and today report the identification of four metabolism-related biomarkers linked to an increased risk of metastatic prostate cancer in men of West African heritage. This discovery could lead to improved testing and treatments for these patients.

The researchers will present their results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2023 is a hybrid meeting being held virtually and in-person Aug. 13–17, and features about 12,000 presentations on a wide range of science topics.

“We have identified genetic and other molecular changes that we hope to develop to predict which Black men are at the highest risk of having their cancer spread,” says Sarah Shuck, Ph.D., the project’s principal investigator, who is presenting the work at the meeting.

“Such a test would give doctors the ability to more accurately predict patients’ prognoses and perhaps design therapies that prevent metastasis,” Shuck says. She is at City of Hope, a cancer and diabetes research organization and cancer treatment center. 

One of the most common malignancies in the U.S., prostate cancer is about 60% more common in Black men than among men of all races, and Black men are twice as likely to die from it, according to statistics from the National Cancer Institute. Diabetes, a chronic condition in which the body’s cells can’t properly pull sugar from the blood, also disproportionately affects Black people and is linked with an increased risk of death for Black men with prostate cancer. 

Shuck’s lab studies the metabolism changes that occur in diabetes and how they can overlap with cancer. This research has included a highly reactive compound known as methylglyoxal, a typical product of metabolism that is elevated in people with diabetes.

Inside cells, methylglyoxal attaches to DNA, RNA and proteins, interfering with their function and promoting the emergence of cancer. Researchers haven’t yet looked at this dynamic in prostate cancer, but they know that, in general, when the complexes accumulate inside and outside of cells, they can drive the spread of cancer.

To find out if these factors play into the racial disparities observed with prostate cancer, the team conducted a small clinical study. Shuck’s collaborators Leanne Woods-Burnham, Ph.D., and Rick Kittles, Ph.D., of Morehouse School of Medicine, gathered blood samples from 371 men with and without prostate cancer from four sites around the U.S. To determine the participants’ race, they assessed samples for genetic evidence of West African heritage. The team, including John Termini, Ph.D., at City of Hope, then looked at four markers associated with methylglyoxal, including the complexes it forms with DNA, RNA and protein. The markers also included variation in a gene, GLO1, that encodes a protein that detoxifies these complexes.

Their analysis uncovered a surprise: Men of West African descent participating in the study had less of these malignancy-promoting complexes in their blood. What’s more, the lower the level of these complexes in the samples, the greater the risk of metastatic disease, contrary to expectations. The researchers speculate that, in this group of men, these complexes become sequestered in tumor cells, spurring on metastatic processes from within. These findings did not apply to men of European descent.

When looking at other potential risk factors, such as body mass index and cholesterol levels, the researchers could not identify anything else that appeared to predict an increased risk of metastasis in the Black participants. In their follow-up research, they plan to continue looking for other risk-predicting variables from within a larger group of participants.

The researchers have their sights set on not only gaining a better understanding of prostate cancer disparities, but also on developing a diagnostic test. “Ultimately, we hope to build a multi-component test doctors could use to predict which Black men are at the highest risk of developing and dying from prostate cancer,” says Shuck.

The researchers acknowledge support and funding from City of Hope’s Health Equities Pilot Grant.

A recorded media briefing on this topic will be posted Tuesday, Aug. 15, by 10 a.m. Eastern time at www.acs.org/acsfall2023briefings.

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Title
Reactive metabolic by-products induced by the exposome are associated with and may drive prostate cancer metastasis in African American men 

Abstract
Prostate cancer (PCa) is the second highest cause of cancer-related deaths in men. African American/Black (AA/B) men are disproportionally impacted by PCa with a 60% higher incidence of disease and a 2-fold increase in mortality risk compared to European American (EA) men. There is an urgent need to elucidate the underlying biological changes that give rise to this disparity to develop inclusive diagnostic and predictive tests and tailored therapeutic treatments. Environmental factors (the exposome) are proposed to contribute to this disparity and can influence disease risk through gene-environment interactions, in which genotypes may influence the response to environmental exposure. A significant contributor to PCa mortality is diabetes incidence, which varies due to the exposome. The mechanisms involved in increased PCa mortality in men with diabetes are not clear but are proposed to arise from physiological changes caused by diabetes-associated metabolic alterations. A proposed mechanism for how these changes increase PCa mortality is through the production of the reactive electrophile methylglyoxal (MG). MG is a by-product of lipid, protein, and sugar metabolism and forms covalent adducts on DNA, RNA, and protein. These adducts, termed MG-advanced glycation end products (MG-AGEs) lead to DNA mutations and genomic instability, change RNA stability and translation, and alter protein stability and function. In addition, MG-AGEs bind and activate the receptor for AGEs (RAGE). To regulate MG and MG-AGEs, cells use glyoxalase 1 (GLO1) to detoxify MG and soluble RAGE (sRAGE) to sequester MG-AGEs and prevent RAGE activation. These components comprise the AGE/RAGE axis. To define the association of MG-AGEs, GLO1, RAGE, and sRAGE with PCa health disparities, we designed a clinical study of AA/B and EA men with and without PCa. We measured serum MG-AGEs using mass spectrometry, serum sRAGE using ELISA, and sequenced the GLO1 and AGER (gene encoding RAGE) loci in genomic DNA isolated from whole blood. We discovered that MG-AGEs, sRAGE, and GLO1 and AGER SNPs were significantly associated with PCa in AA/B men but not EA men. We also observed a significant difference between these components in AA/B and EA men without PCa. This led us to hypothesize that MG-AGEs, sRAGE, and GLO1 and AGER SNPs may have utility as biomarkers for PCa in AA/B men and that GLO1 SNPs may play a role in the accumulation of MG-AGEs, mutations, and PCa cell growth.