PSMA radioligand therapy for solid tumors other than prostate cancer: background, opportunities, challenges, and first clinical reports

Abstract

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

First experiences with 177Lu-PSMA-617 therapy for recurrent or metastatic salivary gland cancer

“…First studies on radionuclide therapy for other solid tumours that express PSMA have recently been summarized [ 19 ]. When compared to glioblastoma, thyroid carcinoma, renal cell carcinoma and hepatocellular carcinoma that all express PSMA in the tumour’s neovasculature and not intracellular, ligand uptake in salivary gland tumours is moderate to weak.…”

Multimodal Imaging-Based Potential Visualization of the Tumor Microenvironment in Bone Metastasis

“…The molecular imaging techniques to visualize the TME in BM are anticipated to expand their role to determine further therapeutic or management plans. Further research is necessary to assess multimodal imaging patterns to examine the TME with newly developed therapeutic targets (including cancer-associated fibroblasts [ 131 ] and neovasculature in tumor tissues [ 132 ]) in patients with BM from various types of cancers. In particular, multidisciplinary approaches are required for the optimization of management based on imaging-aided TME assessment for each metastatic lesion, even in the same patient.…”

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

“…In addition to prostate cancer, several reports showed PSMA upregulation in other tumors, predominantly localized to tumor neovasculature [16][17][18][19]. To determine the PSMA localization in PPGL, we performed immunohistochemical staining on the same set of tumor samples, with the exception of three samples (Nos.…”

“…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]. In addition to prostate cancer, PSMA expression has been demonstrated in several solid tumors [16][17][18][19].…”

“…In pancreatic cancer, PSMA is overexpressed on the tumor cells, where its positive role in folate uptake and cell proliferation has been documented [37]. PSMA expression was also found in several other solid cancers (glioblastoma, kidney, liver, thyroid, lung, and breast cancers), but always localized predominantly in tumor neovasculature, not in normal vessels [16][17][18][19]. In agreement, we have shown PSMA in PPGLs to be localized in the tumor vasculature.…”