Expression of prostate specific membrane antigen (PSMA) in soft tissue sarcomas and urothelial cell carcinomas: implications for tumour-specific molecular imaging and treatment?

Patients with advanced soft tissue sarcoma and advanced urothelial cell
carcinoma have a poor prognosis, with a 3-year survival rate of 20-25% and a
5-year survival rate of 5-40%, respectively. This is due to limited treatment
options and low response rates to systemic chemotherapy of approximately 25% in
soft tissue sarcomas and 40-50% in urothelial cell carcinomas. In these patient
groups there is a high need for new effective treatment options that can
decrease burden of disease and increase survival benefit.

Prostate specific membrane antigen (PSMA) is a transmembrane metallopeptidase
that is overexpressed in prostate cancer cells. For diagnostic purposes, PET/CT
scans that target PSMA have found their way into the clinical routine of
prostate cancer patients. However, currently we know that despite the name,
PSMA is not prostate cancer specific. It is also found in the tumour-associated
blood vessels of a wide variety of other tumours, including soft tissue
sarcomas and urothelial cell carcinomas. In many different sarcoma types, PSMA
expression is seen in the neovasculature with the highest detection rate of
46-60% in high grade and undifferentiated sarcomas (e.g. pleomorphic sarcoma
types). The PSMA expression rate in the neovasculature of urothelial cell
carcinomas still varies in literature, however, the most recently published
article showed that PSMA expression was found in 93% of urothelial cell
carcinoma tissues. Additionally, PSMA expression was seen in the tumour cells
itself in 79% of the tissues. Because of the unique expression pattern which
seems to be limited to tumour cells and tumour-associated endothelial cells,
PSMA may represent an interesting target for molecular imaging using
PSMA-targeting PET scans, and eventually for radionuclide targeted therapy,
when coupled to an alpha- or beta-emitter. [225Act]-PSMA and [177Lu]-PSMA
therapy have shown promising results in the treatment of advanced prostate
cancer patients and might offer perspective and increase quality of life in
patients with advanced soft tissue sarcoma and urothelial cell carcinoma, as
well.

This pilot study aims to investigate the PSMA expression in the biopsy material
of advanced soft tissue sarcomas and advanced urothelial cell carcinomas, and
in case of high PSMA expression, to investigate whether this correlates with
high tracer uptake on PSMA-targeted PET. This way, (a subset of) patients can
be selected that could benefit from radionuclide targeted therapy in the
future.

This pilot study is a single centre, open-label, non-randomized, non-blinded
phase II study with two patient cohorts.

When patients meet the in- and exclusion criteria, immunohistochemical PSMA
staining is performed on already acquired biopsy material, which does not bring
any burden or risks to the study participants. Written informed consent is
required to use the immunohistochemistry results in this study. When high PSMA
expression is found, a [18F]-JK-PSMA-7 PET/CT scan will be made, for which the
patient will need to provide written informed consent as well. For the
[18F]-JK-PSMA-7 PET/CT scan the patient will need to visit the hospital once
for approximately 2 hours. When undergoing PET/CT imaging the patient will be
exposed to radiation with an effective dose of approximately 8.8 mSv. The risk
of adverse effects is low, as the tracer [18F]-JK-PSMA-7 is used on a daily
basis for standard clinical care to perform PET/CT scans in prostate cancer
patients and no adverse effects have been reported. No extra safety
measurements will be taken. Patients do not directly benefit from participation
in this study. In case of high PSMA uptake in the tumours of some patients,
PSMA might provide a target for therapy in future patients.