PSMA-targeting molecules are wonder agents: they can show never-before-seen small bits of prostate cancer dispersed throughout the body. Then, attached to cancer-killing radiopharmaceutical drugs, they can be used to obliterate those spots of metastatic cancer. You can read more about the use of PSMA-targeting small molecules, developed by Johns Hopkins molecular radiologist Martin Pomper, M.D., here.
But wait! There’s more, as PCF-funded investigator Steve Cho, M.D., is proving.
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. In fact, it was with PCF funding that 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 – and that it was safe.
But he wondered: What about the cancer that’s right there in the prostate – cancer that hasn’t spread yet? “There’s a low level of PSMA in the prostate itself. How well does this agent pick up primary prostate cancer?” With a PCF creativity award through Movember, Cho led another study for prostatectomy patients – men with localized prostate cancer who choose to have it taken out surgically. The benefit here is that he 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.” 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.”
