A new study led by Duke Cancer Institute (DCI) researchers offers important insights into that challenge in advanced prostate cancer and could help pave the way for more personalized treatment approaches in the future.
The research, published recently in Cancer and led by Jennifer Freedman, translational scientist with the DCI Center for Prostate and Urologic Cancers, focused on molecules known as ceramides and how they may influence treatment outcomes in patients with metastatic castration-resistant prostate cancer, an advanced form of the disease that continues to grow despite hormone-suppressing therapies.
The study grew out of two innovative Duke-led clinical trials, Abi Race and PANTHER, which enrolled approximately an equal numbers of Black and white patients with advanced prostate cancer. This approach allowed researchers to study treatment outcomes while also examining biological factors that may influence response to therapy.
Studies show Black men are disproportionately affected by prostate cancer, experiencing higher rates of diagnosis, metastatic disease, and death from the disease than other populations. Understanding the factors that contribute to those disparities remains a major research priority.
"We're interested not only in understanding who responds to treatment and who doesn't, but also why," Freedman said. "By building science into clinical trials, we can begin to uncover the biology behind those differences."
Patients enrolled in the studies received androgen receptor pathway inhibitors, a class of therapies that block the effects of hormones such as testosterone that help drive prostate cancer growth. Researchers collected blood samples before treatment and during treatment, allowing them to investigate biological changes associated with therapy response.
In both clinical trials, investigators observed differences in therapy response among Black and white patients. Despite facing a disproportionate burden of prostate cancer overall, Black patients in the first study shifted toward delays in disease progression. And, in the second study, Black patients showed improvements in radiographic progression-free and overall survival.
Previous analysis of samples from the first trial identified genetic variations linked to treatment response. A number of those variations were found in genes involved in ceramide metabolism, leading the team to investigate the ceramides themselves.
Ceramides are lipid molecules that play important roles throughout the body. They are involved in cell growth, cell signaling, cell death, and other essential biological processes. Disruptions in ceramide metabolism have also been linked to the development and progression of cancer.
When the team analyzed blood samples collected before treatment in both studies, they discovered differences in ceramide profiles between Black and white patients. Black patients had lower overall ceramide levels but higher levels of specific long-chain ceramides, which previous research has associated with worse cancer behavior.
As Black patients received androgen receptor pathway inhibitor therapy, levels of potentially harmful long-chain ceramides decreased while levels of shorter-chain ceramides increased. White patients showed the opposite trend, with increases in long-chain ceramides and decreases in shorter-chain versions.
Researchers also identified specific ceramide species that were associated with important clinical outcomes, including disease progression, radiographic progression-free survival, and overall survival. Notably, the ceramides linked to outcomes differed between Black and white patients.
Together, these findings suggest that ceramide metabolism may contribute to how patients respond to hormone-based therapies.
One of the most exciting potential implications of the research is the possibility that ceramides could serve as biomarkers—biological indicators that help predict how a patient is likely to respond to treatment.
If validated in additional and larger patient populations, ceramide profiles could help physicians identify which patients are most likely to benefit from androgen receptor pathway inhibitors and potentially guide treatment decisions earlier during care.
"We can also start thinking about testing combinations of current hormone therapies with treatments that alter ceramide metabolism in models of prostate cancer in the research laboratory," Freedman said. "That approach could potentially improve outcomes even further."
The work represents another example of how laboratory science and clinical research can work together to advance cancer care.
Freedman credits the study's success to the close collaboration between translational scientists and clinical investigators, as well as the decision to integrate scientific research directly into the clinical trials.
The next steps will include validating the findings in additional and larger patient groups and conducting additional studies to better understand how ceramides influence prostate cancer treatment response. Researchers also plan to explore in the laboratory whether targeting ceramide metabolism could enhance the effectiveness of existing therapies.
Ultimately, the goal is to develop more precise treatment approaches and address longstanding disparities in prostate cancer outcomes.
"This is a great example of why it's important to build science into clinical trials," Freedman said. "Every time we learn more about the biology behind treatment response, we're creating opportunities to develop better tools, better therapies, and better outcomes for patients."
