More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

Abstract

Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer.

DOTA Conjugate of Bisphosphonate and PSMA-Inhibitor: A Promising Combination for Therapy of Prostate Cancer Related Bone Metastases

“…Prostate cancer can vary widely in the expression of PSMA. It is known that primary tumors and especially metastases can be PSMA-negative (34)(35)(36)(37)(38). This can also be the case for bone metastases (36,37).…”

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…PSMA is commonly used as a target for prostate cancer imaging and drug delivery. 117 , 118 , 119 , 120 , 121 As boron-containing inhibitors generally had high binding affinity to PSMA, Flavell and co-workers combined PSMA inhibitor scaffolds with boric acids/carborane derivatives, delivering boron into prostate cancer cells and prostate tumor xenograft models ( 20 , Figure 3 L). 119 The results showed that it was feasible to treat low-metastatic prostate cancer with PSMA containing boric acids or carboranes, thus demonstrating the potential role of PSMA in BNCT for the treatment of prostate cancer.…”

Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity

“…PSMA has a large glycosylated extracellular domain responsible for its enzymatic activity, a transmembrane segment, and a short intracellular domain. The short cytosolic tail contains an internalization motif and interacts with various proteins enabling PSMA endocytosis [20]. The molecule is overexpressed in prostate cancer where it correlates with tumor aggressivity and vascularization and it is used as a target for radioconjugates for prostate cancer imaging (FDA approval in 2020) and recently also for therapy of advanced prostate cancer [12,13].…”