Study links ceramide levels to prostate cancer drug response differences

Ceramides-lipid molecules in cells that affect many physiological functions including cell differentiation, migration, and death-and their metabolites have been implicated in the development of cancer and other conditions. New research indicates that different ceramide metabolism in Black and white individuals with metastatic castration-resistant prostate cancer may help explain why they tend to experience different responses to anti-prostate cancer androgen receptor pathway blocking medications. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

In two previous clinical studies, investigators observed differences in response between Black and white individuals who were treated with androgen receptor pathway inhibitors (which decrease or block the effects of hormones such as testosterone) for metastatic castration-resistant prostate cancer. This cancer is a form of advanced prostate cancer that continues to grow and spread even when testosterone is suppressed to castrate levels.

Because certain genetic ancestry-related variants of ceramide metabolism genes were linked to indicators of faster cancer progression in one of those studies, the researchers analyzed ceramide metabolism prior to and during androgen receptor pathway inhibitor therapy in Black and white participants in the two studies.

The team focused on what's called the carbon acyl chain length of ceramides because evidence suggests that ceramides with a 24-carbon acyl chain length promote cell survival while ceramides with a 16-carbon acyl chain length induce cell death. The ratio of 24- to 16-carbon acyl chain length ceramides can influence cancer cells, with higher ratios protecting cells and lower ratios promoting cell death.

When the researchers analyzed trial participants' blood, they found that pretreatment total ceramide levels were lower among Black patients compared with white patients. Among pretreatment ceramides, Black patients had higher values of C24- to C16-ceramide ratios compared with white patients. An opposite trend was seen during treatment, with lower C24- to C16-ceramide ratios among Black patients, whereas higher C24- to C16-ceramide ratios were observed among white patients. Also, certain C16-, C20-, and C24-ceramides were associated with shorter time to cancer progression or worse survival, with differences between Black and white patients treated in the studies.

The two previous clinical studies we conducted were unique with respect to including equal numbers of Black and white patients and collecting trial participants' blood. This created an unprecedented opportunity to explore potential biomarkers that may associate with patient self-reported race and genetic ancestry and treatment outcome. The findings from this research offer valuable observations into ceramide metabolism, including genetic ancestry-related ceramide metabolism, and its potential relationship with prostate cancer outcomes. Continued investigation of genetic ancestry-related ceramide metabolism has the potential to improve prostate cancer outcomes for all patients and mitigate prostate cancer disparities."

Jennifer A. Freedman, PhD, senior author, Duke University School of Medicine