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Diabetes-Related Biomarkers May Have Dx Potential for Predicting Prostate Cancer Risk in Black Men

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NEW YORK – A set of biomarkers previously linked to diabetes has shown potential in predicting which Black men are at increased risk of metastatic prostate cancer.

At a meeting of the American Cancer Society, Sarah Schuck, an assistant professor in the department of diabetes and cancer metabolism at City of Hope, shared results from a study, which demonstrated how physiological changes caused by diabetes-associated metabolic dysregulation contribute to increased prostate cancer risk in Black men.

Black men are 70 percent more likely than white men to be diagnosed with prostate cancer, and their risk of dying from the disease is two-to-four times higher than men of other racial and ethnic backgrounds. Black men and women also have higher rates of diabetes and are twice as likely to die from it than non-Hispanic white adults. "We wanted to understand if diabetes might be driving this aggressive prostate cancer risk," Schuck said. 

She and her colleagues identified a highly reactive compound, methylglyoxal, which when elevated in diabetics may drive prostate cancer. Methylglyoxal is a metabolic byproduct that forms covalent complexes with DNA, RNA, and protein, known as MG-advanced glycation end products (MG-AGEs). These complexes lead to genomic instability, and in response, cells regulate the MG-AGEs through two enzymes which detoxify and sequester them.

Schuck's team gathered blood samples from 371 men with and without prostate cancer who were previously enrolled in a clinical trial conducted by Tanya Dorff, a medical oncologist at City of Hope, with co-investigators Rick Kittles, senior VP for research at Morehouse Medical School, and Leanne Woods-Burnham, an assistant professor of physiology at Morehouse.

The researchers then measured four potential biomarkers related to diabetes in the samples. They assessed MG-AGEs using mass spectrometry and the receptor that sequesters MG-AGEs (sRAGE) via an immunoassay. They also sequenced the gene encoding glyoxalase 1 (GLO1), which detoxifies methylglyoxal and the gene encoding the MG-AGE receptor (AGER).

These studies showed that MG-AGEs, sRAGE, and single nucleotide polymorphisms in the GLO1 and AGER genes were significantly associated with prostate cancer in Black men, but not white men. There were also differences in those markers between Black and white men without prostate cancer.

Because the methylglyoxal complexes are believed to promote cancer by binding to DNA and RNA, Schuck and her team expected markers related to methylglyoxal to be elevated in Black men with prostate cancer compared to white men. However, the association was opposite from what Schuck expected.

"In Black men, the levels of circulating metabolic markers were lower compared to white men," she said. "That was surprising to us at first. We are now hypothesizing that perhaps there is an accumulation of these markers inside the tumor cells that might be driving tumor growth." Thus, the lower level of methylglyoxal complexes seen in blood samples from Black men may be due to tumor cells not releasing them.

The researchers also collected data on clinical variables such as smoking status and BMI, but in Black men, the only variable that was associated with metastatic prostate cancer was the set of biomarkers related to methylglyoxal. "We really want to understand why that is and how [these markers] might not only be biomarkers of disease, but also drivers," Schuck said. In white men, smoking status was the only variable associated with metastatic prostate cancer.

MG-AGEs are notable in diabetes, but they are also linked to conditions such as inflammation and obesity. "In the health disparities context, there might be ways to understand how different access to health care, different diet, [and] different exposures to certain conditions can lead to the risk of metastatic prostate cancer, as well," Schuck said.

One of the limitations of this study was that there were no biopsy or tumor samples available from the patients. Schuck's group is now developing in vivo mouse xenograft models using tumor cells from white and Black men to see if exposure to high blood glucose levels will lead to accumulation of methylglyoxal complexes inside cells and become a driver of tumor growth and metastasis.

Schuck and her collaborators eventually want to incorporate these biomarkers into a diagnostic test that predicts Black men's risk of developing and dying from prostate cancer. She envisions a test that can track reduced levels of methylglyoxal complexes or related gene expression levels in blood samples. Schuck is also exploring the possibility of a noninvasive test by assessing how quickly these markers are cleared in urine samples in animal studies. "We're hoping from our animal models, we'll be able to figure out a more comprehensive picture of how these molecules are metabolized and what they look like in different areas of the body," Schuck said.

Although in the study researchers used samples from Black men with West African ancestry according to a genetic test, Schuck said it will not be necessary to screen patients for West African ancestry before conducting diagnostic testing. That’s because in the study, the researchers did not find a correlation between the methylglyoxal complexes with West African ancestry, or that ancestry associated with the risk of metastatic prostate cancer. “In our context, that was really used as a way to very accurately determine if a person was Black or white,” Schuck explained, since most studies of this kind rely on self-reported race, which isn’t always accurate.

And although the biomarkers identified in the study are implicated in diabetes, Schuck said the difference in biomarker levels between Black and white men was significant independent of whether or not the men had diabetes. As such, a prostate cancer risk test developed based on these biomarkers would be applicable to all Black patients, she said, not only Black patients with diabetes.

Results of such a test could then be used by the patient's physician to predict his prostate cancer risk and tailor standard therapies to that risk level. Schuck noted that because the methylglyoxal complexes bind to DNA and RNA, this same set of biomarkers could point to therapies that target DNA damage and DNA repair pathways such as PARP inhibitors. "Our hope in prostate cancers and other types of cancers is to understand how specific classes of drugs might work efficiently in these patients," Schuck said.

Other studies Schuck's group is planning in this line of research include investigating the pharmacokinetics of methylglyoxal complex formation in response to hyperglycemia and how those complexes drive tumor growth as well as validating the current study findings in an independent cohort.

Schuck said her group is also very interested in studying these same markers in triple-negative breast cancer and are hoping to use specimens collected within the California Teachers Study. In that large, long-term project, researchers are gathering health data from members of the California State Teachers Retirement System and have enrolled over 100,000 participants to date.