Maybe you’ve been diagnosed with high-risk prostate cancer. Maybe you have already been treated for prostate cancer, but your PSA is starting to creep back up, which means that the treatment didn’t get all of the cancer – but maybe it’s just right there in the prostate area, easily targetable with radiation. Or maybe it’s just in one lymph node, or it’s in a transition state called oligometastasis: not widespread, but in just a few isolated spots outside the prostate. In other words, maybe the cancer can still be cured – if you can just find it.
It’s called PSMA PET imaging, and it works kind of like a heat-seeking missile. A radioactive tracer that lights up in a PET scan is molecularly engineered to find one very specific target: PSMA (prostate-specific membrane antigen), a protein that lives in high concentrations on the surface of most prostate cancer cells. Because the tracer is injected systemically, it can shine a virtual spotlight on whatever it tags – even tiny bits of prostate cancer – anywhere in the body. Several of these tracers have been studied, and one, called 68Ga-PSMA-11, was recently FDA-approved for use at two hospitals in California: UCLA and UCSF. Another agent called 18F-DCFPyL (PyL), developed at Johns Hopkins by a team led by Martin G. Pomper, M.D., Ph.D., Director of Nuclear Medicine and Molecular Imaging, is the latest to receive FDA approval and will be more widely available.
Both of these PSMA-targeting agents got their start with PCF funding. “What we are seeing is decades of research now bearing clinical fruit,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of PCF. “PCF has long believed in the promise of PSMA targeting – not only for imaging cancer, but for a revolution in how to treat it. Over nearly 30 years, since 1993, we have invested more than $28 million in research on PSMA, with the goal of finding cancer that has escaped the prostate when it is very early and at a very small volume, because we believe that this will help us change the course of metastatic prostate cancer.”
PyL has proven itself in two important clinical trials: CONDOR, published in Clinical Cancer Research, and OSPREY; published in the Journal of Urology. In the OSPREY trial, PyL PET/CT was tested in two groups of patients: 1) men just diagnosed with high-risk prostate cancer who were set to undergo radical prostatectomy with pelvic lymphadenectomy, and 2) men with metastatic or recurrent cancer. In the first group, the ability of PyL to detect any metastases in pelvic lymph nodes or beyond was determined, and in the second group, PyL was used to detect distant metastases.
In the CONDOR study, men with a rising PSA after treatment for prostate cancer with surgery, radiation, or cryotherapy, who had no visible cancer on standard imaging were scanned with PyL PET/CT, which accomplished what researchers hoped it would: “PyL successfully localized sites of disease in 85% of men with biochemical recurrence,” says Pomper, “even men with low PSA levels. It detected and localized disease in most men with biochemical recurrence presenting with negative or equivocal conventional (bone scan plus CT) imaging, and led to changes in management in the majority of patients.”
For many doctors and patients, this new FDA approval of PyL can’t come soon enough, says Pomper. “I’ve had patients for years asking me when we are going to be able to use this. It’s taken a long time, but we are finally there.”
In 2002, Pomper was the first to figure out how to engineer a small-molecule, harmless radioactive tracer to PSMA. With PCF funding, he and his team went on to test the first PSMA-targeted PET agent in a clinical trial. This he refined into PyL, a more sensitive and specific second-generation agent that provides sharper images. “With standard imaging (bone scans and CT), we may suspect there is cancer outside the prostate area, but we often just can’t see it in its earliest stages. Standard imaging is not good enough for detecting and characterizing disease in men with biochemically recurrent prostate cancer, particularly in men with a low PSA (less than 2). But 95 percent of prostate cancer has PSMA.” And as Johns Hopkins radiation oncologist Phuoc Tran, M.D., Ph.D., and others are showing in clinical trials of oligometastasis, very small, isolated bits of prostate cancer are now being considered treatable – and possibly curable – targets.
How is PyL different from 68Ga-PSMA-11? The differences are nearly negligible except for one: 68Ga-PSMA-11 requires special equipment to make, has a short half-life, and must made in small batches on site in the medical center. 18F-DCFPyL (trade name PYLARIFY®) has a longer half-life and thus can be made by a company and shipped to any medical center able to perform PET imaging. Although this is a radioactive compound, it is well-tolerated, says Pomper. “It doesn’t affect you like a medicine; it’s given in trace doses. It just binds to PSMA and goes away; it doesn’t do anything else to your body.”
PSMA-Targeting Can Kill Cancer, Too!
But wait! This is not all that PSMA-targeting can do! Instead of attaching the tracer molecule to “see” a cancer cell, you can attach a radioactive drug to kill the cancer. In Europe and Australia, and in international clinical trials, PSMA-targeting radionuclides, such as 177Lu-PSMA-617 are being used to target and kill cancer in just those tiny outposts, leaving nearby cells undamaged. This is killing prostate cancer cells at the level of hand-to-hand combat, and it is a bright spot on the horizon as a treatment option for men with metastatic prostate cancer.
What about the cancer cells that don’t make PSMA? This, too, is on the horizon: Pomper is developing new molecules and therapies to target “PSMA-invisible” forms of prostate cancer. “It took a long time, but now we’re seeing many exciting offshoots of our work in other forms of cancer, as well. Some pretty amazing things are happening. And PCF was there, funding this at the very beginning.”