Armstrong Speaks on New Cell Surface Targets for Advanced Prostate Cancer
Published
Multiple new cell surface targets are being investigated in advanced prostate cancer to hopefully lead to more effective therapies. Andrew Armstrong, MD, director of research for the Duke Cancer Institute Center for Prostate and Urologic Cancers, spoke with Clinical Advances in Hematology & Oncology about these developments.
Cell surface targets are more accessible and engageable than other targets, making them more effective for therapies in solid tumors and hematologic malignancies. Armstrong said ideal cell surface targets are highly expressed in cancer cells and missing in normal cells, so therapies avoid damaging healthy tissue.
Eight cell surface targets have received approval from the U.S. Food and Drug Administration (FDA) for treatment; only one of those targets, prostate-specific membrane antigen (PSMA), applies to prostate cancer.
“The hope is that in the future, researchers will make use of cell surface targets to develop new antibody-drug conjugates, radioligand therapies, bispecific or trispecific antibodies, and chimeric antigen receptor (CAR) T-cell or natural killer/myeloid cell therapies,” Armstrong said.
Investigations are currently underway to uncover cell surface targets for the three biological disease states of prostate cancer – adenocarcinoma, NEPC/small cell prostate cancer, and poorly differentiated prostate cancer. Each state has different cell surface proteomes, requiring tailored treatments.
PSMA has already shown to be effective in typical prostate adenocarcinoma. Other targets, including STEAP1, hK2 and B7-H3, are being explored for treatment.
Before administering these treatment options to patients, Armstrong said it is important to ensure durable responses and improved patient outcomes. Safety monitoring is also crucial, since targets could potentially be expressed in normal tissues. Finding adequate biomarkers with analytic and clinical viability also proves difficult.
“Biomarker development needs to be intentional from the start because biomarkers must go through phases 1, 2, and 3 as a companion diagnostic, in line with drug development,” Armstrong said. “Biomarkers should be an integral part of the studies submitted for FDA approval to optimize dosing and patient benefit while minimizing toxicity and exposure to potentially harmful therapies in patients for whom treatment will be ineffective.”
Research from the DCI Center for Prostate and Urologic Cancers focuses on prevention and screening, early diagnosis, and the development of new treatments, including targeted treatments and individualized care. Learn more about the center.
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."
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."
