Advancing Radiotheranostics at Duke Through Prostate, Neuroendocrine Cancer Research
Published
Radiotheranostics is a rapidly evolving field that combines targeted imaging and therapy using radiolabeled molecules. At Duke Cancer Institute, researchers are exploring new opportunities for this therapeutic approach in prostate and neuroendocrine cancer care through strategic clinical trials and interdisciplinary collaboration.
Neuroendocrine Cancer: Building on a Legacy of Innovation
Michael Morse, MD, medical oncologist with the DCI Gastrointestinal Cancer disease program, has had a longstanding collaboration with the Division of Nuclear Medicine and Radiotheranostics, particularly with nuclear medicine specialist Terence Wong, MD, PhD. Morse, Wong, and their teams have worked together integrating imaging and radiopharmaceutical treatment of neuroendocrine tumors (NETs).
Duke was one of the early leaders in this research through work with I-131 MIBG, a radiolabeled compound previously used for treating neuroendocrine tumors, pheochromocytomas, and paragangliomas.
More recently, Duke participated in the NETTER-1 trial which led to the FDA approval of Lu177-dotatate (Lutathera®) for gastroenteropancreatic NETs. The institution played a key role in subsequent compassionate use programs and has since become one of the leading centers in the Southeast for Lutathera® administration.
More recently, Duke has been a top U.S. recruiter for the COMPOSE trial, a study comparing ITM-11, a novel lutetium-based therapy, to standard for patients with intermediate and high-grade neuroendocrine tumors.
Morse also highlighted Duke’s opening of the BELU-RE trial, a national study evaluating Lutathera® in patients with pulmonary NETs, a group currently excluded from the FDA-approved indication of this drug. He said the growing interest in radioligands based on alpha emitters like Actinium-225 and Lead-212 offers higher energy and more potent DNA damage than traditional beta emitters.
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“Duke’s involvement in radiotheranostics clinical research has given our patients early access to these drugs which are assuming an increasingly important role in neuroendocrine tumor therapy.”
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Michael Morse
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Medical Oncologist, DCI Gastrointestinal Cancer disease program
Prostate Cancer: Expanding the Boundaries of Radioligand Therapy
In the prostate cancer space, Daniel George, MD, co-chair of the DCI Center for Prostate and Urologic Cancers, is leading efforts to expand the use of radioligand therapies beyond their current FDA-approved indications.
“For men with castration-resistant metastatic prostate cancer, the clock is ticking,” George said. “Their average survivals are around three years. Radioligand therapies deliver lethal radiation specifically to tumors, which can improve patient outcomes.”
Vipivotide tetraxetan (PLUVICTO®) is currently approved for treatment of patients with metastatic castration-resistant prostate cancer, but the institution is exploring ways to enhance its efficacy and broaden its application. One strategy involves combining PLUVICTO® with DNA repair inhibitors, aiming to prevent cancer cells from recovering from radiation-induced damage.
Another promising avenue is the use of Actinium-225, an alpha emitter that delivers significantly more radiation per molecule than the beta emitting lutetium-177, potentially improving cell kill rates with greater precision.
Researchers at Duke are also investigating alternative targets like KLK2, a prostate cancer surface bound molecule like PSA, through trials that combine KLK2-targeted radioligands with chemotherapy or use them in post- PLUVICTO® settings. These studies aim to address unmet needs in patients with resistant or heavily pretreated cancers.
The institution is also preparing to launch trials in high-risk localized prostate cancer, administering radioligand therapy prior to prostatectomy. This approach could offer curative potential by eradicating microscopic disease beyond the surgical field, potentially reducing the need for hormonal therapy.
Additionally, Duke investigators will explore radiotheranostics in kidney cancer, targeting CA-9 with novel imaging and therapeutic agents currently under FDA review.
A Vision for the Future
Morse and George emphasized the importance of adaptive and personalized approaches to radiotheranostics. As trials evolve, research teams will look at refining dosing strategies, tailoring treatments based on tumor response, and leveraging advanced imaging to guide therapy decisions.
“These studies are more complicated and require a lot of coordination,” George said. “They require specialized infrastructure and expertise only available at centers of excellence like Duke.”
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."
