(UroToday.com) For radioligand therapy to be performed, the ligand needs to be radiolabeled with the isotope; it will need to be injected to the patient, allowing it to bind to the target of our choice. It is important to make sure that the target is being overexpressed using imaging based on the same ligand before the administration of radioligand therapy.
There are several available radioisotope emitters, as can be seen in Figure 1. The first physical property to consider when choosing an isotope emitter is its decay mode that will define the linear energy transfer, which is defined as the amount of energy transferred to the cell that will eventually result in DNA damage. There is a total of 3 types of decay modes that are of interest to us (Figure 2):
- Alpha – causing double-strand DNA breaks
- Beta – causing single-strand DNA breaks
- Auger e – causing multiple strand DNA breaks
Figure 1 – Known available emitters:
Figure 2 - Types of Linear energy transfer of radioisotope emitters:
Next, Mathieu Gauthe, MD, moved on to discuss the differences between the three most commonly used emitters, as shown in Figure 3.
Figure 3 – Common Nuclide properties:
In the next part of his talk, Dr. Gauthe elaborated on the different targets being used for ligands. The first discussed target is the prostate-specific membrane antigen (PSMA), which is a transmembrane type II glutamate carboxypeptidase, overexpressed by 90-95% of prostate cancer cells. Its receptor density increases in high grade and metastatic prostate cancer, in castration-resistant prostate cancer (CRPC), and as an effect of androgen-deprivition therapy (ADT) in hormone-sensitive prostate cancer cells. Dr. Gauthe then presented some of the more recent studies assessing the results of PSMA ligands in radioligand therapy in CRPC patients (Figure 4). These studies demonstrate a mean of 50% response manifested as a more than 50% PSA decrease compared to the pre-therapeutic value.
Figure 4 – Studies assessing PSMA ligands for radioligand therapy in CRPC patients:
Dr. Gauthe moved on to discuss the clinical perspective of ligands.
He began with Neurotensin, which is a 13 amino acid neuropeptide, secreted by the enteroendocrine cells of the small intestine, and distributed throughout the central nervous system. NTSR1 is a transmembrane coupled receptor G protein overexpressed in cancers with oncogenic effects. It has been shown that the NTSR1 expression level in prostate cancer exceeds that of non-malignant prostate cells (92% vs. 8%). Importantly, there is a high or moderately increased expression of NTSR1 in all PSMA-negative tissue.
Fibroblast activation protein (FAP) is another studied ligand, which is a type 2 transmembrane serine protease, expressed on the cell surface of activated stromal fibroblasts of 90% of epithelial tumors. However, it is also expressed in wound healing and fibrotic diseases, causing false positives, and it promotes tumorigenesis of tumor cells. It has intermediate to high uptake in PSMA negative patients and in CRPC (Figure 5).
Figure 5 – Comparison of ligands:
The last discussed ligand is the Bombesin (gastrin released peptide), which is a 14 amino acid peptide which stimulates gastrin release from G cells. Bombesin receptors are transmembrane receptor G protein-coupled with low expression in high-grade prostate cancer, CRPC, and bone metastases. However, there might be an interest in using it for the treatment of earlier stages of prostate cancer.
Dr. Gauthe concluded his talk stating that emitters have to be chosen according to the target tissue, considering the decay mode and the maximal emission energy and half-life (delivered dose). It is essential to also consider the damage caused to tumor cells in comparison to that caused to normal cells by this type of therapy.
Although PSMA ligands have demonstrated promising results in the treatment of CRPC patients, there is still data lacking regarding survival advantages, and whether they are significant.
There are currently a few potential future theranostic targets for CRPC, including Neurotensin receptors, inhibitors of fibroblast activation protein, and Bombesin receptors. All these will require evaluation in larger studies.
Presented by: Mathieu Gauthe, MD, Hospital Tenon, Paris, France
Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan, at the 35th Annual EAU Congress, 2020 Virtual Program #EAU20, July 17-19, 2020.