Establishing Radiolabelled PSMA as a Target for Glioma Treatment

One potential avenue of high grade glioma treatment involves a 'theranostic' radiotherapeutic approach. This consists of two stages: firstly, a particular protein expressed specifically by the tumour is radiolabelled with a targeted radioligand emitting gamma radiation, enabling confirmation of the presence, concentration and distribution of this target protein (diagnostic stage). Following this, a similar ligand is this time attached to an alpha or beta-emitter, enabling targeted tumour destruction (therapeutic stage).

There is growing, but limited, evidence that prostate specific membrane antigen (PSMA) is strongly and specifically expressed in high grade glioma and may be a potential theranostic target [Wernicke 2011, Unterrainer 2017]. It has already been used extensively as a theranostic target in metastatic prostate cancer, demonstrating safety and efficacy in this condition [Abou et al 2020].

The clinical outcomes shown in prostate cancer, along with evidence of PSMA expression in high grade glioma, led the study team to convene an Incubator Day with a group of experts to explore the possibility of developing a PSMA-targeting theranostic agent in high grade glioma. Expertise included PSMA theranostics (Prof Lewington), neuro-oncology (Dr Brazil, Guy's and St Thomas' Hospital (GSTT)), neurosurgery (Prof Ashkan, King's College Hospital (KCH)), neuropathology (Prof Al-Sarraj, KCH), neuroradiology (Dr Booth, KCH) PSMA PET imaging (Prof Gary Cook and Prof Alexander Hammers GSTT/KCL), nuclear physics (Prof Paul Marsden GSTT/KCL), and PSMA radiopharmaceutical chemistry (Prof Blowers, KCL).

It was concluded that a PSMA-targeting theranostic agent has the potential to be a safe and effective treatment for high grade glioma. The regulatory pathway should be eased enormously by the precedent of use in prostate cancer, which would obviate the need for pre-clinical studies.

This approach was conditional upon two objectives:

• Perform a series of five [68Ga]PSMA PET scans for dosimetry analysis and assessment of the retention of the tracer in the tumour (Using GSTT/KCL PET/MRI) prior to biopsy, at the same time as the patient's routine brain tumour imaging series. At time of recurrence a further [68 Ga]PSMA PET-MRI scan may be performed in each patient (depending on whether or not recurrence occurs during the study period) to assess for change in the standardised uptake value (SUV).
• Performing immunohistochemical analysis on high grade glioma specimens (prospectively in patients enrolled in this study with additional retrospective samples), in order to replicate published evidence on the expression of PSMA in such tumours, and also to demonstrate in the prospective cohort, a correlation between imaging detection of [68 Ga]PSMA and histopathological detection in stereotactic brain tumour biopsy samples (Using KCH neuropathology facilities).

Inclusion criteria

• Individuals of 18 years or older
• Referred for surgery (resection or biopsy) of presumed high grade primary brain tumour (based on imaging features of aggression e.g. perfusion imaging, diffusion restriction etc.). As standard, all patients will have had a full body CT and other investigations to rule out metastatic disease (this has a very high negative predictive value).
• Written informed consent

Exclusion criteria

• Patient already enrolled in a drug trial
• Contra-indication for MRI contrast
• Contra-indication for radiotracer
• Inability to give consent
• Patient is pregnant or planning to become pregnant