Genitourinary medical oncologist Dr. Michael Morris is part of a new MSK program focused on better treatments for neuroendocrine cancers, which sometimes develop when prostate and lung cancers become drug resistant.
The good news is that treatments for prostate cancer are helping patients live longer. But an unsettling new challenge is emerging: a different and deadlier form of the cancer called neuroendocrine prostate cancer (NEPC). Researchers at Memorial Sloan Kettering Cancer Center (MSK) are confronting it with multiple new research projects and clinical trials.
“MSK played a major role in developing treatments for adenocarcinomas, the most common form of prostate cancer,” says MSK genitoruinary medical oncologist and prostate cancer section head Michael Morris, MD. “But now we are seeing how these advances are producing resistant disease in some people when prostate cancer returns.”
What Is Neuroendocrine Prostate Cancer (NEPC)?
NEPC usually arises when adenocarcinoma develops resistance to treatments such as certain hormonal therapies. This form of the disease now develops in 15% of patients receiving hormone therapy. And it’s especially lethal: There are currently no therapies available for NEPC, and life expectancy is less than 18 months after diagnosis.
MSK Moves to Meet a Need to Treat NEPC
This urgent need is motivating a new program at MSK focused on NEPC.
“No other program in the country really has this combination of laboratory experience, diagnostic tools, and therapeutic clinical trials to offer these patients, who otherwise have no standard treatment options,” Dr. Morris says.
MSK Research Shows How NEPC Develops
In recent years, pioneering research by physician-scientist Charles Sawyers, MD, and computational biologist Dana Pe’er, PhD, showed that prostate cancer cells can escape the effects of hormone therapy by completely changing their identity from adenocarcinoma to neuroendocrine cancer.
This transformation throws up a major diagnostic and therapeutic roadblock. The cancer may no longer make the proteins — including prostate specific antigen (PSA), found in a blood test, and prostate specific membrane antigen (PSMA), found in the prostate cancer cells themselves — that allow the disease to be detected and targeted.
Targeting DLL3 in NEPC With Treatment Using Radioactive Imaging
To treat and diagnose NEPC effectively, MSK researchers identified a new target: a ligand (molecule) called DLL3. This ligand is especially prominent in NEPC as well as in small cell lung cancer (SCLC), an aggressive form of that disease.
In 2024, a team led by radiochemist Jason S. Lewis, PhD, and physician-scientist Charles M. Rudin, MD, PhD, reported promising results testing a new imaging agent that targets DLL3. Results from the pilot study showed that the imaging agent reliably detected cancer cells containing DLL3 in 18 patients. An accompanying commentary in The Lancet Oncology called the research “a pivotal milestone” that is “notable for its scientific novelty and the potential to improve patient outcomes.”
“In the short term, this technology could be essential for finding out whether a patient should receive a DLL3 drug or a different therapy,” Dr. Rudin says. “And if we can link the imaging agent to drugs or therapeutic isotopes, we would have an important new treatment option for these prostate and lung cancers.”
There is good reason to be optimistic that this approach could lead to better diagnosis and treatment for neuroendocrine cancers. In 2022, the U.S. Food and Drug Administration (FDA) approved a similar imaging agent for detecting and treating metastatic adenocarcinoma by focusing on PSMA.
Grant to Help MSK Advance DLL3-Based Treatment for NEPC
MSK has been awarded multiple grants to continue developing and validating the DLL3-based technology — most notably an $8 million grant from the Prostate Cancer Foundation to Dr. Lewis, Dr. Morris, and other MSK colleagues.
Dr. Lisa Bodei
“Prostate cancer and lung cancer are two of the most common, so we are talking about a huge potential impact on patients’ lives,” Dr. Morris says.
Nuclear medicine physician Lisa Bodei, MD, PhD, who is Director of Targeted Radionuclide Therapy at MSK, is working with nuclear medicine physician Mark Dunphy, DO, and Dr. Rudin to develop and test other radioactive therapies. They are collaborating with Salomon Tendler, MD, PhD, a research fellow in Dr. Lewis’ lab.
Clinical Trials for Neuroendocrine Prostate Cancer and Small Cell Lung Cancer
MSK offers an array of clinical trials for people with NEPC and small cell lung cancer. Some have already opened, while others will begin enrolling soon. Most of the treatments being tested target DLL3:
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A clinical trial led by Dr. Bodei is opening soon that will test a radioactive ligand that targets DLL3 in people with metastatic NEPC and small cell lung cancer. Patients will first receive the DLL3 imaging agent to determine whether DLL3 is present in sufficient quantities. If so, they will receive the imaging agent coupled with a radioactive isotope. The therapy will target the cancer cells and leave normal cells unharmed.
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A trial led by MSK genitourinary medical oncologist Karen A. Autio, MD, MSc, will test a new immunotherapy drug called tarlatamab (Imdelltra™) in people with NEPC. Tarlatamab has already been approved for treatment of DLL3 small cell lung cancer. The trial is being conducted in collaboration with the University of California, San Francisco.
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Medical oncologist Alissa J. Cooper, MD, is helping lead a phase 1/2 trial testing an immunotherapy drug called MK-6070 in people with DLL3 cancers. The study, sponsored by Harpoon Therapeutics, will test MK-6070 alone and in combination with other drugs. Learn more about this trial.
- Radiologist and nuclear medicine physician Vetri Sudar Jayaprakasam, MBBS, is helping lead a trial using radiotherapy to target three proteins at once (PSMA, SSTR2, and GRPR) in people with NEPC. Learn more about this trial.
“We are the only institution that can offer patients with this disease the most accurate diagnosis and opportunity to receive the latest treatments through clinical trials,” Dr. Morris says. “If one doesn’t seem effective, there are others we can try, and more will become available down the road.”
The therapeutic advances in neuroendocrine cancer treatment stem largely from MSK’s unique collaboration between basic scientists and clinicians.
“It’s amazing to have the kind of research meetings where all the parties are sitting together,” Dr. Dunphy says. “We have incredible radiochemistry experts who talk about how to design new imaging or treatment technologies. And then our oncology experts will say, ‘Don’t chase after that one. Here’s what is clinically relevant to us.’ There’s this constellation of stellar investigators brainstorming a realistic vision of the future.”
