A small molecule that targets both FAP and PSMA? They’re on it!

Two huge advances have dramatically changed the diagnosis and treatment of metastatic prostate cancer, and both of these involve prostate-specific membrane antigen (PSMA), a molecule that sits on the surface of prostate cancer cells. PSMA-targeting radiotracers, including a small molecule-based agent developed at Johns Hopkins (commercially available as PYLARIFY), allow a PSMA-PET scan to show where prostate cancer is hiding anywhere in the body – even as small as a grain of rice. And a different radiation-emitting particle attached to that same PSMA-targeting molecule (177LuPSMA-617, available as Pluvicto) tracks down these same cancer cells and kills them.

This is a whole new field called “radiotheranostics” (an approach using one radioactive drug to find the cancer, and another radioactive drug to treat it), and these are remarkable, highly promising advances. But: although some people have had exceptional responses to PSMAtargeting radiotherapy, nobody is calling it a cure. It is a treatment that “has proven beneficial compared to the standard of care in metastatic castration-resistant prostate cancer (mCRPC),” says scientist Sangeeta Ray, Ph.D., M.S. With Martin Pomper, M.D., Ph.D., Director of Nuclear Medicine and Molecular Imaging, Ray has been working to develop new agents for molecular imaging and therapy for 17 years.

The problem, she explains, is that mCRPC is heterogeneous: it is made up of many different types of cancer cells. Some of these don’t make a lot of PSMA (which means the PSMA-targeting tracer can’t show where they are hiding), and some of them don’t make PSMA at all.

“Lesions that are PSMA-negative – for example, neuroendocrine prostate cancer – can represent particularly aggressive disease,” Ray notes. Fortunately, she and Pomper have found another target: Fibroblast activation protein alpha (FAP), another molecule that sits on these potentially lethal cancer cells. It is abundant, she says, and a characteristic of all mCRPC.

FAP-targeting small molecules have already been developed by the Hopkins team and others “for FAP-based PET imaging to detect PSMA-negative metastatic lesions.” What about a small molecule that targets both FAP and PSMA? They’re on it! “We hypothesized that a small molecule agent targeting FAP and PSMA might enhance cancer detection and therapy for targeting all prostate cancers, including those without PSMA, and neuroendocrine cancer. Such a strategy has the potential to overcome the limitations of current PSMA-radiotherapeutics.”

To test this hypothesis, the team developed an optimized agent (64Cu-FP-L1) attaching the FAP- and PSMA-targeting small molecules and tested them in relevant preclinical, experimental models of prostate cancers.” The results were exciting: “This new agent demonstrated high and specific tumor targeting of FAP and PSMA expression.” The next step is to see how well this dual-targeting agent will work as a potential treatment. Future studies are under way. This work was published in the European Journal of Nuclear Medicine and Molecular Imaging.