31 August 2021

Reducing Lethal Prostate Cancer in Men with African Descent

Research Insights with Stefan Ambs, PhD, MPH

One in seven African-American men will develop prostate cancer in his lifetime. Overall, African-American men are 2.2 times more likely to die from prostate cancer than white men. What is the cause of this discrepancy, and what can be done about it?

Stefan Ambs, PhD, MPH, Senior Investigator and Head of the Molecular Epidemiology Section in the Laboratory of Human Carcinogenesis at the National Cancer Institute (NCI), is hoping to decrease the burden of this aggressive disease by offering reasons for this disparity.

In a Geneva-managed study titled “A Precision Medicine Study of How Inflammation May Underlie the Excessive Burden of Prostate Cancer in Men of African Ancestry,” Dr. Ambs is collaborating with Tuskegee University Center for Biomedical Research and partnering Principal Investigator Clayton Yates, PhD to explore – for the first time ever – the relationship between systemic/chronic inflammation, ancestry, and tumor biology as a cause of disease progression in men of African descent.

Epidemiology of Prostate Cancer

Dr. Ambs conducts integrative epidemiology studies of prostate cancer and breast cancer and utilizes epidemiological and translational research to identify risk factors and pathways that influence tumor development and progression. He has authored and co-authored close to 140 research manuscripts and his work has been cited more than 15,000 times.

Creating an understanding of how the interaction between chronic inflammation and tumor biology affects prostate cancer progression in African-American men offers the opportunity to develop improved prevention and therapeutic strategies using anti-inflammatory drugs and immune modulators to decrease the disease burden among all men.

“While equal access to care is the key target to improve cancer survival,” said Dr. Ambs, “we now know that there are differences in disease biology and risk factor exposure across population groups.”

Systemic low-grade inflammation is a prostate cancer risk factor in men of African descent and correlates with West African ancestry, a distinct tumor biology, and aggressive disease. “Our overall objective is to understand these relationships, and how the social environment contributes to it, with a view to informing prevention and therapeutic strategies,” said Dr. Ambs.

Dr. Ambs and others have shown in research that prostate tumors in African-Americans harbor a distinct immune inflammation signature. Low-grade inflammation has been described as a prostate cancer risk factor that is associated with aggressive disease. In a manuscript he co-authored, he indicates that regular aspirin use reduces the risk of aggressive prostate cancer and disease recurrence in these men.

“Together, the observations suggest that a systemic low-grade chronic inflammation related to the social environment, ancestral factors, and tumor biology could be a contributing cause to the excessive prostate cancer mortality in men with African ancestry,” said Dr. Ambs. “Yet, and unexpected, men of African descent with prostate cancer may have a favorable response to certain immune therapies because of the presence of inflammation and a related immune biology.”

Sequencing DNA and RNA Patient Samples

Dr. Ambs and his team aim to measure 97 markers in plasma/serum or urine to examine their association with prostate cancer, genetic ancestry, family history, and lifestyle factors and build a database.

After processing thousands of blood (about 3000) and urine (about 2000) samples from men with and without prostate cancer in the NCI-Maryland and NCI-Ghana prostate cancer studies, the samples were shipped to laboratories across the U.S. to obtain measurement data. These labs include Olink, measuring immune-inflammation markers; OmegaQuant, testing for omega-3 fatty acid levels; Leidos Biomedical Research measuring lipopolysaccharide; and the Eicosanoid Core Laboratory at Vanderbilt University, to measure urinary metabolites of the cyclooxygenase signaling pathway to compare levels of these markers between men of African ancestry and men of European ancestry and to relate their levels to risk factors and lethal prostate cancer.

Preliminary Research Findings

With data for blood and urine markers in hand, the research team has begun analyzing the data.

As an initial step – to examine whether the abundance pattern of 82 immune-oncology markers is distinct by population group –  researchers found that levels of these markers indeed associate with the three population groups in the study, comparing African American, Ghanaian, and European-American men. The researchers also recently reported that increased signaling by thromboxane A2, a metabolite mainly produced by platelets, associates with metastatic and lethal prostate cancer in African American men and inversely correlates with aspirin use (PMID: 34264335). A serum proteomics signature was discovered that links suppression of tumor immunity to ancestry and lethal prostate cancer. These findings connect the inflammation and immune environment in the circulation to the odds of developing a prostate cancer metastasis, affecting African American men more so than European-American men.

“The findings are consistent with our hypothesis that a unique systemic immune-inflammation signature might exist in men of African ancestry,” said Dr. Ambs.

Next Steps

The team will begin the analysis of the genomics data coming from the analysis of prostate tumors.

With the recent finding by Oliver Sartor, PhD and colleagues that the cancer vaccine, Sipuleucel T, may especially improve survival of African American men with metastatic castration-resistant prostate cancer, “interest in the immune-inflammation signature in prostate tumors of African-American men has surged.”

Dr. Ambs said, “We believe that the research questions that we pursue under this award will have important implications for immune therapy in African-American men with otherwise lethal prostate cancer.”

 

This award number WH81XWH-18-1-0588 was funded by the Defense Medical Research and Development Program, Prostate Cancer Research Program, Impact Award – Partnering PI Option and the U.S. Army Medical Research and Materiel Command.

 

Disclaimer: The views expressed do not reflect the official policy of the Army, the Department of Defense, or the U.S. Government.