Scientists at City of Hope have identified a cell metabolism process found in men with diabetes and metastatic prostate cancer that could one day lead to improved testing and treatments for Black men with these diseases. The research was highlighted at the American Chemical Society (ACS) Fall 2023, a hybrid meeting held virtually and in person in San Francisco from Aug. 13 to 17.
Prostate Cancer in Black Men
Black men are more than twice as likely than other men to die from prostate cancer. In a continued search to develop inclusive diagnostic and predictive tests and personalized treatments, City of Hope researchers conducted a small clinical trial that identified four metabolism-related biomarkers linked to an increased risk of metastatic prostate cancer, or prostate cancer that has spread to other parts of the body, in men of West African heritage. City of Hope leads the nation in having the first research department focused on the intersection between cancer and diabetes.
“Men with diabetes are at a significantly higher risk of developing metastatic prostate cancer, and this is exacerbated in Black men. We were interested to find out if markers that measure how well a person is managing their diabetes might be associated with metastatic prostate cancer,” explained Sarah Shuck, Ph.D., principal investigator of the trial, who presented the data at ACS. Shuck is an assistant professor in the Department of Diabetes & Cancer Metabolism within the Arthur Riggs Diabetes & Metabolism Institute at City of Hope.
As a result of the study, “We have identified genetic and molecular changes that can be developed into a tool to predict which Black men are at the highest risk of developing metastatic prostate cancer,” Shuck said. “This test would give doctors the ability to more accurately predict patients’ prognoses and equip scientists with more data as they work to design therapies that prevent prostate cancer from developing in the first place,” Shuck added.
The problem appears to be production of a highly reactive compound known as methylglyoxal (MG), a byproduct of metabolism that is elevated in people with diabetes. MG binds to DNA, RNA and protein, creating a complex that may promote cancer emergence due to its creation of cellular instability and disrupted function. “Methylglyoxal is a by-product of many metabolic pathways that are altered in many people with diabetes and that are also associated with tumor growth,” Shuck explained. “We have seen similar results in triple-negative breast cancer, a deadly form of breast cancer that disproportionately affects Black women.”
Prostate cancer is the second most common cancer in men. Black men are 70% more likely than white men to be diagnosed with prostate cancer and two to four times more likely than other racial and ethnic groups to die from the disease, according to 2023 data from the American Cancer Society.
Diabetes’ Link to Prostate Cancer
Diabetes is a chronic metabolic disease characterized by elevated levels of blood glucose, or sugar, which over time leads to serious damage to the heart, blood vessels, eyes, kidneys and nerves. Black adults are 60% more likely than white adults to be diagnosed with diabetes and twice as likely to die from diabetes, according to the most recent data available from the U.S. Department of Health and Human Services Office of Minority Health.
Shuck’s lab focuses on the study of how metabolic dysregulation causes diabetes and cancer. She and her colleagues investigate the biochemistry involved when excess sugar damages important molecules. To see if the identified dysregulated complexes were linked to race and genetics, the team conducted a clinical study where they gathered blood samples from 371 men with and without prostate cancer from across the nation. To determine race, they assessed samples for genetic evidence of West African heritage using methods developed by collaborators Rick Kittles, Ph.D., M.S., and Leanne Woods-Burnham, Ph.D., who were at City of Hope when the research was conducted.
Next the researchers, including John Termini, Ph.D, professor in the Department of Cancer Biology and Molecular Medicine at City of Hope, looked at four biomarkers associated with MG and the complexes it forms with DNA, RNA and protein. The biomarkers also included variation in a gene, GLO1, that encodes a protein that detoxifies these complexes.
Prostate Cancer Screening
Surprisingly, the men of West African descent had fewer of these malignancy-promoting complexes in their blood. Contrary to expectations, a lower level of these complexes was linked to greater risk of metastatic disease. The researchers hypothesize that, in men of West African descent, tumor cells sequester these complexes and spur metastatic processes from within. In other words, “We think that the levels of methylglyoxal complexes are lower in [blood] circulation because they are accumulating in the tumor and driving tumor growth,” Shuck said. These findings did not apply to men of European descent.
City of Hope researchers intend to gain a better understanding of prostate cancer disparities in the hopes of developing a diagnostic test.
“We hope that our findings can become part of a comprehensive clinical panel that can be used to predict the risk of deadly prostate cancer.” Shuck said. “Specifically, we anticipate that these tools can be used to determine which men with diabetes are at the highest risk of metastatic prostate cancer. The goal is to give physicians the ability to determine which men will respond best to specialized treatments and potentially identify new therapeutic targets.”