Remember these letters: PSMA. If you haven’t heard of PSMA-targeted agents yet, you probably will soon.
Imagine a heat-seeking missile – except the tiny target locked onto by this particular missile is PSMA (prostate-specific membrane antigen), a protein that sits on the surface of prostate cancer cells. The weapon itself is a small molecule, originally designed as an imaging agent by a team led by Johns Hopkins investigator Martin Pomper, M.D., Ph.D., and scientists are still discovering what it can do.
How specific is it? Imagine a bit of tissue the size of a teardrop. Two of the cells inside it are prostate cancer cells; the rest are not. With a PSMA-targeting tracer, like Pomper’s small molecule or any of its next-gen relatives, only those two cells would light up.
We’re talking molecular LEGOs here: With Pomper’s small molecule, PSMA can be linked to different chemical bricks. One kind of brick is a radioactive tracer that can show on a PET scan exactly where small bits of cancer are hiding. But wait! There’s more: PSMA can also be hooked up to a radiopharmaceutical agent, called a radionuclide, that can seek out and kill those tiny pockets of cancer and potentially even stop metastatic disease.
It’s like the old commercial for the miracle product called Shimmer on “Saturday Night Live.” It’s a floor wax! It’s a dessert topping! No, it’s both!
“It truly has excellent potential and we are just scratching the surface here of what PSMA-targeting can do,” says medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, “in metastatic disease and also in localized disease.” I recently interviewed Simons and Pomper for the PCF’s website, and Pomper for the newly released Fourth Edition of my book with Patrick Walsh.
This momentum has been building for two decades. “We started working on PSMA-based imaging agents back in the late 1990s,” says Pomper, Director of Nuclear Medicine and Molecular Imaging at Johns Hopkins. Pomper’s team was not the first to try to harness PSMA as a way to get to prostate cancer; in 1996, scientist Neil Bander created an antibody that can target PSMA and used SPECT imaging to see hidden prostate cancer cells. But antibodies are cumbersome; it takes several days from the time they are administered until they clear the bloodstream and reach the target cells. They are also very large. Continuing the building-block theme here, it’s like trying to attach toddler-friendly DUPLO blocks to the much more svelte LEGOs. “We want to be able to scan within an hour or so after injection,” Pomper explains. “We prefer the small molecules for therapy, too.”
Pomper’s versatile small molecule and derivatives of it have galvanized the field of nuclear medicine. PSMA-targeted imaging and therapy has generated huge interest worldwide – especially in Europe, where scientists have linked the small molecule to radionuclides (both alpha- and beta-emitting particles) and are reporting long-term remissions in some men with metastatic prostate cancer. “You just switch what’s attached to the small molecule, and you can go from imaging to irradiating the cancer – cancer you can’t even see, potentially. This would be impossible using external-beam radiation.”
German doctors – who, thanks to a regulatory loophole were able to move right into using PSMA-targeted radiotherapy without having to conduct the clinical trials required in the U.S. – have even reported cures in a few men – but also some side effects, including the loss of the salivary gland, where some PSMA-bearing cells also live. That’s because, although scientists called it “prostate-specific,” PSMA is not solely confined to prostate cancer.
Scientists worldwide are trying to figure out how to tackle the “collateral damage” problem of PSMA. Is there some way to protect the salivary gland, like using potassium iodide to protect the thyroid in the event of a nuclear attack? Some of the salivary-protecting options being explored include botox and anticholinergic drugs.
The Great Promise of PSMA-Targeting Agents
“PSMA is present in the normal prostate, present in the brain, the kidney and the intestines,” Pomper notes, “but it’s really expressed much higher in malignant prostate tissue. It’s also expressed in the neovasculature – the vessels tumors need in order to grow in place or metastasize.”
PSMA is present in many different cancers, too. “Renal cell carcinoma, glioblastoma, pancreas cancer and other cancers have PSMA in the blood vessels around them – not in the tumor itself,” and this is an exciting potential avenue for future research: finding a way to target and kill PSMA-bearing areas around some terrible cancers that desperately need effective treatment.
Pomper keeps tinkering with the molecule and agents that link to it.. Recent work with Hopkins colleagues in Radiology and Radiation Oncology has led to the first published small-molecule alpha-particle emitting agent to treat prostate cancer. A team led by radiation oncologist Ana Kiess, M.D., Ph.D., linked an alpha-particle emitter to Pomper’s small molecule. “Alpha particles are emitted from certain molecules as a consequence of radioactive decay,” explains Pomper. “They are useful for treating cancer because they provide a lethal punch to the DNA of malignant cells – more so than other forms of radiation. The key is to enable the alpha emitter to reach the cancer cells selectively, leaving normal tissues unharmed.”
In the lab, “using this agent, we were able to prolong the lives of immunocompromised mice bearing human prostate tumors,” says Pomper. This study lays the groundwork for future clinical trials in men with prostate cancer, and for the design of even safer, next-generation alpha particle agents. Also, it “represents a pivot by our group from developing imaging agents to finding better agents for therapy.” The group is now leading a phase I clinical trial for beta particle-emitting agents it has developed.
The very good news for men with advanced prostate cancer is that numerous clinical trials are opening in the U.S. and Australia to test similar PSMA-targeted radiopharmaceutical agents. In fact, the PCF is funding three research projects – in Australia, at UCLA, and Weill Cornell – and all of these have clinical trials.
PSMA-PET Can Help Clarify Localized Prostate Cancer, Too
So far, efforts with PSMA-targeting molecules have mostly been focused on what ancient Romans called the disjecta membra, the scattered bits and pieces of cancer that started out in the prostate and moved to the lungs, bone, liver, or someplace else.
But what about the cancer that’s right there in the prostate – cancer that hasn’t spread yet? That’s what investigator Steve Cho, M.D., has been working to find out. Cho, on the faculty at Johns Hopkins before joining the faculty at the University of Wisconsin, led the first human imaging study of Pomper’s PSMA-targeting agent. He showed how well PSMA-PET could pick up metastatic prostate cancer – better than a bone scan and CT combined. Then he thought: “There’s a low level of PSMA in the prostate itself. How well does this agent pick up primary prostate cancer?” With Movember funding through the Prostate Cancer Foundation, Cho led another study for prostatectomy patients – men with localized prostate cancer who have it taken out surgically. The benefit here is that Cho and colleagues could compare what they saw on the PSMA-PET images with what the pathologists found in the needle biopsy tissue and in the actual removed prostate specimens. They learned a couple of very important things:
One, in localized disease “this specific agent doesn’t show up in all prostate cancer patients.” (Note: other PSMA-targeting molecules might be found to work better in this situation.) But “it does show up in men with higher-grade cancers,” Gleason grade 8 or 9 tumors.
As it turns out, PSMA-targeting molecules have discernment.
This is really important, because many men need some extra help. “One of the problems with MRI,” Cho explains, “is that it can pick up a lot of lesions – but sometimes they are benign.” Calculi, stones in the prostate (like kidney stones, but tiny), and enlargement of the prostate (BPH) can show up on an MRI, too, and it’s not always apparent what needs to be treated and what doesn’t.
MRI is sensitive, but not always very specific; it’s “user-dependent, in terms of interpretation and experience.” Understandably, a radiologist who looks at nothing but prostate images all day probably has more expertise at spotting prostate cancer than does a radiologist who looks at images of all sorts of body parts. “PSMA-PET was specific in our study,” says Cho. “If you see a signal by PSMA-PET in the prostate, it typically ends up being a site of prostate cancer, and ends up being clinically significant.”
This could be particularly helpful for men with an elevated PSA but a negative biopsy (or biopsies), or men considering Active Surveillance for prostate cancer. Men who are told they have low-grade disease – because the biopsy needle hasn’t picked up anything different – could have extra peace of mind if a PSMA-PET comes up negative for high-grade disease. Or, men who have had one or more inconclusive biopsies may decide to undergo surgery or radiation therapy if PSMA-PET shows high-grade cancer that the needles missed.
Even if a biopsy shows cancer, “the biopsy needle is not always accurate,” Cho notes. “It might show Gleason 6 disease, but maybe there’s Gleason 8 cancer somewhere hidden. ” Similarly, during a rectal exam, “the urologist’s finger can’t always feel cancer in the apex or anterior of the prostate. That’s where I think this technology can really help: it can provide a better way of targeting a specific region of the prostate so the needle has a higher probability of a true hit.”
Combining PSMA-PET with MRI may result in even more accurate and predictive scans, as well.
But wait again! There’s even more! Cho is exploring PSMA-PET in several different studies, aimed at helping men with different stages of prostate cancer.
One of these is for men with high-risk prostate cancer, “we currently have a clinical trial here at the University of Wisconsin, a Department of Defense-supported grant, with medical oncologist Joshua Lang, M.D., urologist David Jarrard, and biomedical engineer David Beebe, Ph.D., who studies the microenvironment of tumor cells. “In these high-risk patients, at the time you take the prostate out, they already have a high probability of having cancer outside the prostate.” But if the disease could be attacked systemically, with three months of hormonal therapy (Degarelix) and chemotherapy (Docetaxel) before prostatectomy, would that help – and could PSMA-PET images show that tiny bits of cancer have disappeared?
In future studies of men with advanced prostate cancer, Cho envisions using PSMA-PET to monitor treatment – any kind of treatment – to make sure it’s working. “Can we tell early on whether a patient is responding or not responding well, so we don’t have to continue to give treatment that’s not working, and we can quickly change course?” Molecular imaging can help doctors “be more nimble” and respond more quickly – either to intensify treatment or, if it’s working, perhaps to dial it back and spare the patient multiple cycles of hormonal therapy or chemotherapy. This is already happening in other cancers, such as lymphoma.
“This whole area is evolving,” says Cho. “We have barely scratched the surface.”
We’ll be talking more about PSMA in future posts.
In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.” As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.
©Janet Farrar Worthington