Pharmacological Optimization of PSMA-Based Radioligand Therapy

Abstract

Prostate cancer (PCa) is the most common malignancy in men of middle and older age. The standard treatment strategy for PCa ranges from active surveillance in low-grade, localized PCa to radical prostatectomy, external beam radiation therapy, hormonal treatment and chemotherapy. Recently, the use of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) for metastatic castration-resistant PCa has been approved. PSMA is predominantly, but not exclusively, expressed on PCa cells. Because of its high expression in PCa, PSMA is a promising target for diagnostics and therapy. To understand the currently used RLT, knowledge about pharmacokinetics (PK) and pharmacodynamics (PD) of the PSMA ligand and the PSMA protein itself is crucial. PK and PD properties of the ligand and its target determine the duration and extent of the effect. Knowledge on the concentration-time profile, the target affinity and target abundance may help to predict the effect of RLT. Increased specific binding of radioligands to PSMA on PCa cells may be associated with better treatment response, where nonspecific binding may increase the risk of toxicity in healthy organs. Optimization of the radioligand, as well as synergistic effects of concomitant agents and an improved dosing strategy, may lead to more individualized treatment and better overall survival.

Keywords: PSMA; lutetium; optimization; pharmacodynamics; pharmacokinetics; prostate cancer; radioligand; theranostics; therapy; variability.

Figure 1

Schematic overview of the structure of a PSMA receptor. DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; PSMA = prostate-specific membrane antigen.

Figure 2

(a) Physiological pathway of androgens and regulation of PSMA receptors. DHT coupled to the androgen receptor has an inhibiting effect on the production of PSMA receptors; (b) Androgen blockage, for example, by enzalutamide, causes an upregulation of the PSMA receptor due to the loss of the inhibiting effect. DHT = dihydrotestosterone; AR = androgen receptor; PSMA = prostate-specific membrane antigen.

Figure 3

Simplified crosstalk between androgen receptor pathway and PI3K-AKT pathway. DHT = dihydrotestosterone; AR = androgen receptor; PI3K = phosphoinositide-3-kinase; PIP2 = phosphatidylinositol(3,4,5)-biphosphate; PIP3 = phosphatidylinositol(3,4,5)-triphosphate; PTEN = phosphatase and tensin homolog; AKT = protein kinase B; mTOR = mammalian target of rapamycin.