The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research

Abstract

Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA has shown to be an excellent target for PCa theranostics because of its high expression on the membrane of PCa cells and the increase in expression during disease progression. Therefore, numerous PSMA-targeting tracers have been developed and (pre)clinically studied with promising results. However, many of these PSMA-targeting tracers show uptake in healthy organs such as the salivary glands, causing radiotoxicity. Furthermore, not all patients respond to PSMA-targeted radionuclide therapy (TRT). This created the necessity of additional preclinical research studies in which existing tracers are reevaluated and new tracers are developed in order to improve PSMA-TRT by protecting the (PSMA-expressing) healthy organs and improving tumor uptake. In this review we will give an overview of the recent preclinical research projects regarding PCa-TRT using PSMA-specific radiotracers, which will give an indication of where the PSMA-TRT research movement is going and what we can expect in future clinical trials.

PSMA PET/CT Identifies Intrapatient Variation in Salivary Gland Toxicity From Iodine-131 Therapy

“… 25 This was recently applied to salivary glands to reduce PSMA uptake. Although the impact was limited, 26 given the promising outcomes of radiolabeled PSMA therapies (such as 177 Lu, 225 Ac, and 213 Bi) for prostate cancer, for which xerostomia can also be a significant side effect, 27 this further supports PSMA PET/CT as a tool to evaluate strategies for sparing the salivary glands in different types of radionuclide therapies.…”

Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy

“…PSMA has become one of the most researched and promising PCa targets in the last decade, for the improvement of (metastasized) prostate cancer care. The focus of preclinical research has predominantly been on altering the chemical structure of the tracers, creation of bi-ligands (ligands that are specific for two targets), and the use of different therapeutic radionuclides to improve PSMA-TRT [9] resulting in an overwhelming number of novel radiolabeled PSMA-targeting tracers. Evaluation and comparison studies on existing high potential tracers are urgently needed to further support selection of PSMA-targeting tracers for theranostic purposes.…”

“…The difference between both small molecule inhibitors with regard to composition and length of the linker is most likely the reason for the difference in binding. Various examples in literature highlight the impact of linker composition on binding characteristics and biodistribution of PSMA-targeting compounds [9]. For example, the replacement of the 2-naphthylalanine amino acid of the linker of PSMA-617 with the 3,3diphenylalanine amino acid (creating HTK01167) led to a 6× lower renal binding and a 2× lower tumor binding [36].…”

“…PSMA-positron emitting tomography scans have shown PCa (oligo)metastases that were untraceable with conventional methods which logically led to the development of PSMAspecific tracers suitable for targeted radionuclide therapy (TRT). The excellent theranostic application of PSMAtargeting compounds resulted in the development of various tracers of which the most promising were tested in clinical trials; these are showing promising results [7][8][9]. However, the expression of PSMA in healthy organs, such as the small intestine, central nervous system, proximal renal tubules, prostate, and especially the salivary and lacrimal glands, can lead to serious side effects, which may strongly affect the quality of life of the treated patients [10][11][12].…”

“…To date, DOTA-PSMA-617 and DOTAGA-PSMA-I&T (further referred to as PSMA-617, PSMA-I&T) are the most often applied small molecule inhibitors for PSMA-TRT and PCa diagnostics. These tracers share the same PSMA-binding motif, and both comprise a DOTA or DOTAGA chelator that can be labeled with therapeutic or diagnostic radionuclides, respectively [9,14,15]. Currently, lutetium-177-labeled PSMA-I&T and PSMA-617 are being examined separately in a phase II and phase III clinical trial [16,17].…”