PSMA beyond the prostate: exploring prostate-specific membrane antigen as a target in the treatment of late-stage malignancies of the thyroid, liver and the head and neck

Patients with head and neck cancer, hepatocellular carcinoma or iodine refractory thyroid cancer have a poor prognosis, with a respective 5y overall survival of approximately 50%, 15% and 20 %. Patients can be confronted with severe complaints caused by therapy resulting in a detrimental impact on the quality of life. Moreover, adjuvant therapies are often insufficient to achieve cure or long-term remission when a patient is diagnosed with metastatic disease. There is thus a great need for new diagnostic and therapeutic interventions to improve these patients' survival and quality of life. The prostate-specific membrane antigen (PSMA) is heavily expressed on the membrane of most prostate cancers. Besides enabling improved imaging of prostate cancers using PET/CT, PSMA is used as a novel therapeutic target and targeting PSMA using the therapeutic radionuclide 177Lu has shown to increase survival in patients with metastatic prostatic cancers. However, the protein’s name was wrongly chosen, as PSMA is also expressed in the tumor-induced neovasculature of solid cancers. Significantly, PSMA expression in these solid cancers was associated with a worse prognosis. Consequentially, immunohistochemical demonstration of PSMA expression by the tumor and PSMA-directed imaging using PET/CT might enable a distinction between patients with high- and low-risk disease. We hypothesize that the destruction of these blood vessels with 177Lu-PSMA might increase survival in these patients. Furthermore, because of the increased necrosis, PSMA-targeted radionuclide therapy might also increase the impact of other systemic therapies such as chemotherapy or immunotherapy. In conclusion, results from this project could enable a more individualized tumor-specific therapy with better survival for the patient.