Researchers at MSK have helped pioneer major advances that will enable doctors to pinpoint the location of prostate cancer cells more precisely than ever before so they can be targeted with personalized treatments. The researchers also have begun to solve an enduring mystery about how some metastatic prostate cancers escape powerful drugs.
The most immediate breakthrough involves a new form of imaging.
“This is the biggest diagnostic advance for prostate cancer since the 1980s, when the PSA [prostate-specific antigen] test was introduced,” Dr. Morris says. “Imaging has been the Achilles heel of prostate cancer because the disease is hard to detect after it has spread, forcing many treatment choices to be based on estimation and probabilities. Now, we can be much more confident that we are correctly identifying the location of the disease to make an accurate treatment plan.”
The new technology uses a radioactive substance that selectively seeks out and attaches to a specific protein on the cancer cell surface. The protein, called prostate-specific membrane antigen (PSMA), is not found on most normal cells. When the radioactive tracer binds to the prostate cancer cells, they show up as bright spots on a PET scan.
“With PSMA PET, we can now detect the cancer cells directly and much earlier than we could with standard CT or PET scans,” he says. Dr. Morris played a leading role in clinical trials testing a particular tracer that is easy to manufacture and can be used at all institutions. MSK radiologist Hebert Alberto Vargas and interventional radiologist Jeremy Durack were key collaborators in the development and testing of the tracer.
In May 2021, the FDA approved this tracer — the first for national, widespread use. The PSMA advance is the result of years of work by MSK’s Molecular Imaging and Therapy Service, led by Heiko Schöder.
This technology has an even more exciting potential: zeroing in on prostate cells to destroy them. A therapy called 177Lu-PSMA-617 selectively binds to PSMA in prostate cancer cells and delivers DNA-damaging radiation, killing the cell. Patients receive this treatment by injection over six sessions, usually spaced six weeks apart, given by nuclear medicine physicians.
“Effective treatments for metastatic prostate cancer have been limited, so this could be a game-changer,” Dr. Morris says.
Just ask Michael Rosenblum. In 2019, his prostate cancer had become resistant to treatment and had spread to his bones. His PSA levels — a marker that normally should be in the single-digit range — had soared to more than 100.
Dr. Morris enrolled Michael in a clinical trial led by nuclear medicine physician Lisa Bodei testing the benefits of 177Lu-PSMA-617 when used in combination with standard prostate cancer therapy. Since Michael’s last treatment in February 2020, the 75-year-old has been free of symptoms. His scans have improved, and his PSA is less than 1. He just celebrated his 50th wedding anniversary.
“I had no side effects, either on the day of the procedures or afterward,” Michael says. “My PSA went right down, and my blood tests have been really good. From how I feel today, you would never think I had cancer a few years ago.”
Dr. Morris presented results from the trial, involving more than 800 patients with advanced prostate cancer, at the American Society of Clinical Oncology meeting in early June 2021. Men who received the drug had a median of 8.7 months of progression-free survival — the period when the disease didn’t worsen — compared with 3.4 months for those receiving only standard treatment. Side effects were not serious. Among the most common was dry mouth.
In mid-June 2021, the treatment received Breakthrough Therapy designation from the FDA. This designation is used to help speed the development and review of therapies that demonstrate the potential to be a substantial improvement over available treatments.
“We hope this therapy will receive FDA approval,” says Dr. Morris, whose research has been supported by the philanthropy of the Magnier family.
For Dr. Morris, the recent inroads against this stubborn disease — the second leading cause of cancer death in men — are especially gratifying. “I have been involved in the PSMA research since the end of my fellowship at MSK in the late 1990s,” he says. “The benefits these advances will bring to men with this common disease cannot be overstated.”
Another promising effort to help patients with metastatic prostate cancer is being led by physician-scientist Charles Sawyers, the Marie-Josée Kravis and Henry R. Kravis Chair in Human Oncology and Pathogenesis.
Dr. Sawyers is focused on fighting drug resistance, based on lessons he learned from pioneering the lifesaving treatment imatinib (Gleevec®) to treat chronic myeloid leukemia (CML). Imatinib targets an abnormal protein and essentially cures CML — a landmark in targeted cancer therapy.
But Dr. Sawyers discovered cancer cells could become resistant to imatinib. This raised the question of whether a different mechanism had taken over to promote the cancer. Researchers wondered if they were still focused on the right target. Dr. Sawyers’ instincts told him to zero in even more closely on the abnormal protein, believing it was the scene of the crime.
“When you play the game Clue and think the murder happened in a certain room, that’s the room you go to,” he says. “With CML, we discovered that we had the right target but that the protein was mutating. It didn’t completely solve the problem, but it led to important insights into how resistance develops.”
Dr. Sawyers says he remembered this lesson when his research shifted to prostate cancer. He put a bullseye on a protein called the androgen receptor (AR), which all prostate cells need — prostate cancer cells in particular — to survive and grow. Staying focused on AR allowed researchers, including Dr. Sawyers, to develop several AR-blocking drugs that have improved survival for advanced prostate cancer.
But some metastatic prostate cancers still evade destruction. “We make smarter and more potent AR inhibitors, and the tumors still escape,” Dr. Sawyers says.
In the last few years, he and MSK colleagues have made a startling discovery: Some metastatic tumor cells actually change their identity to survive. This transformation, known as lineage plasticity, allows prostate cancer cells to no longer depend on the androgen receptor.
To undergo this change, the cancer cells must have certain genetic mutations. Dr. Sawyers says focusing on those mutations should make it possible to know which patients will have cancers that are shape shifters.
“At one level, this is scary because it says that a tumor has the ability to once again outsmart our drugs,” Dr. Sawyers says. “But we really understand this at a much better level than we did just a few years ago.”
Dr. Sawyers says he benefits greatly from the expertise of MSK colleagues. For example, medical oncologist Charles Rudin had noticed similar plasticity in lung cancer cells — during treatment, the tumors transformed from adenocarcinoma to small cell lung cancer. When the two researchers realized they had found the same intriguing phenomenon, they decided to collaborate to investigate it further. Dr. Rudin and Dr. Sawyers, along with their lab members, began meeting regularly to trade notes and share insights.
Dr. Sawyers’ team is also collaborating with Sloan Kettering Institute computational biologist Dana Pe’er, a world-renowned expert in single-cell analysis. This powerful new technology enables researchers to look closely at individual cells to determine which genes are expressed, or “turned on.” This makes it possible to get a clearer picture of how the mutations cause cells to change.
“This is similar to the challenges I faced earlier in my career with leukemia in that we’re getting to that moment of clarity that will allow us to catch this transition in its earliest stages,” Dr. Sawyers says. “That gives us a treatment strategy for these prostate cancer patients when the drugs stop working.”