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PSMA Theranostics: Is the Time Ripe to Pave the Way to Further Tumor Entities?

Success of precision oncology is based on increasingly better and individualized tumor characterization. State-of-the-art personalized treatment options are still primarily directed by site of tumor origin and tumor entity rather than by the tumor molecular signature (e.g., the novel treatment approach with neurotrophic tyrosine receptor kinase [NTRK] inhibitors in the case of NTRK gene fusion– positive tumors) irrespective of their origin. Molecular imaging using metabolic tracers and radiolabeled peptides and antibodies offer a unique possibility for noninvasive in vivo tumor characterization, also based on molecular paradigms rather than tumor type. One such radiopharmaceutical, the prostate-specific membrane antigen (PSMA), is currently set to become a blockbuster for both PET diagnostics and radionuclide therapy in prostate cancer. Germany, specifically the University of Heidelberg team, has pioneered the rejuvenation of PSMA and its use in nuclear medicine. The evidence level from initial retrospective German studies was substantiated by subsequent prospective clinical trials in Australia. The proPSMA diagnostic trial reported that “PSMA PET/CT is a suitable replacement for conventional imaging, providing superior accuracy to the combined findings of CT and bone scanning” in treatment-naïve patients with high-risk prostate cancer with respect to detection of both pelvic nodal and distant metastases (1,2). Similarly, PSMA PET/CT proved also superior in detecting local recurrences, lymph node, or distant metastases in patients with early biochemical relapse and rising prostate-specific antigen levels as low as 0.2 ng/mL (3). These findings support recent U.S. Food and Drug Administration (FDA) approval of 2 new drug applications for PSMA PET imaging at the Universities of California San Francisco and Los Angeles for both primary staging in high-risk prostate cancer patients and patients with biochemical recurrent disease. The findings also reinforce the recommendation for PSMA PET imaging in the setting of biochemical recurrence in the recently updated national German S3 guideline on prostate cancer (4) and reimbursement of this procedure within the framework of Ambulante Spezial€artzliche Versorgung in Germany. Most recently, the PSMA tracer F-piflufolastat from Lantheus was approved by the FDA (5). Additionally, major progress in the realm of PSMA treatment in patients with prostate cancer has been made. The results of the international, prospective, open label, multicenter, randomized phase 3 study of Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (VISION trial) showed that Lu-PSMA-617 significantly increased overall survival and radiographic progression-free survival in these patients (6). PSMA-based theranostics, therefore, very soon will increasingly become a clinical standard in prostate cancer patients—as long as these tumors express PSMA. But PSMA is by far not as prostate-specific as suggested by its name. It is a type II transmembrane zincmetallopeptidasewith enzymatic activity that hydrolyzes poly-g-glutamated folates to folate, which can be taken up by nearby tumor cells (7). The enzyme is also known as glutamate carboxypeptidase II, folate hydrolase 1, folypoly-g-glutamate carboxypeptidase, and N-acetylated-a-linked acidic dipeptidase I. PSMA is physiologically expressed in astrocytes and Schwann cells of the nervous system, prostate, proximal renal tubule of the kidney, salivary glands, and the duodenal brush border (8) as can be seen and quantified on PET images of cancer patients (9). In malignant tumors, however, PSMA expression is not only documented for prostate cancer cells but also found in the tumorassociated neovasculature of almost all solid tumors though not in normal vasculature. Interestingly, PSMA expression often correlates with the aggressiveness of tumors, as has been shown for prostate cancer as well as other tumor entities, for example, sarcomas in which PSMA expression was higher in more malignant tumors (10). A comprehensive review on PSMA PET imaging of nonprostatic diseases has been recently compiled by de Galiza Barbosa et al., in which a variety of different tumors, including almost all relevant carcinomas as well as brain and nerve-derived tumors, lymphomas, and softand bone tissue sarcomas, were shown to be PSMA-positive, usually related to endothelial expression in the associated neovasculature. The authors therefore concluded that “these unintentional findings have paved the way for the application of PSMAPET imaging as an additional diagnostic tool” (11). These “unintentional” findings of PET-detectable PSMA expression inmany differentmalignant tumors imply potential use not only for imaging but also for therapy: it may open up a universal theranostic approach of tumor treatment inmany tumors, and, thus, should be followed in more detail for different tumor entities, especially in tumors with a high medical need for therapy improvement. Among all the nonprostatic PSMA-expressing tumors, aggressive brain tumor glioblastoma multiforme (GBM) holds special mention as treatment results in this tumor type, despite extensive research, are still very poor with no curative options thus far. Initial results in 16 Received Jun. 13, 2021; revision accepted Jun. 29, 2021. For correspondence or reprints, contact Winfried Brenner (winfried. brenner@charite.de). Published online July 16, 2021. COPYRIGHT 2021 by the Society of Nuclear Medicine andMolecular Imaging. DOI: 10.2967/jnumed.121.262737