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.

Keywords: PET/CT imaging; Prostate-specific membrane antigen (PSMA); Radioligand therapy; Solid tumors; [177Lu]Lu-PSMA; [68 Ga]Ga-PSMA.

Fig. 1

FOLH1 expression levels of cancers included in TCGA PAN-CAN Atlas studies. This figure was adapted from cBioportal.org. Cancers are sorted based on median. Negative values are the result of the log(2) scale, where expression of 0 up to 1 in log(2) scaling results in negative values. Overall expression of mRNA in other cancers is considerably lower (log scale) than that in prostate cancer. All cancers show a large variation in FOLH1 expression levels. Abbreviations: ACC adrenocortical carcinoma, AML acute myloid leukemia, DLBC diffuse large b-cell lymphoma, pRCC papillary renal cell carcinoma, RCC renal cell carcinoma, PCPG pheochromocytoma and paraganglioma, Uterine CS uterine carcinosarcoma, GBM glioblastoma multiforme, LGG lower grade glioma, ccRCC clear cell renal cell carcinoma

Fig. 2

Four example PSMA PET/CT whole-body images of patients with salivary gland cancer, thyroid cancer, hepatocellular carcinoma, and breast cancer. A Patient with adenoid cystic carcinoma (salivary gland cancer) showing PSMA ligand uptake in lung metastases with a mean SUVmax of 10.0 and tumor-to-liver ratio of 2.5. B Patient with papillary thyroid carcinoma where PSMA PET/CT showed medium–high PSMA uptake in pulmonary metastases (median SUVmax 8.0). Additionally, new hotspots were seen on PSMA PET/CT (compared to [¹⁸F]FDG PET) in the left cervical lymph nodes (SUVmax 3.33) and liver (SUVmax 7.2). C Patient with hepatocellular carcinoma showing focal uptake with an SUVmax of 17.6 and tumor-to-liver ratio of 4.0, as well as a tiny lesion in the cutting line with an SUVmax of 8.4. D Patient with breast cancer where PSMA PET/CT imaging demonstrated multiple osseous metastasis and a primary right breast cancer. Patient A was originally published in van Boxtel et al., [⁶⁸ Ga]Ga-PSMA-HBED-CC PET/CT imaging for adenoid cystic carcinoma and salivary duct carcinoma: a phase 2 imaging study, Theranostics 2020, Ivyspring International Publisher© [33]. Patient B was originally published in de Vries et al., [⁶⁸ Ga]Ga-PSMA PET/CT in radioactive iodine-refractory differentiated thyroid cancer and first treatment results with [¹⁷⁷Lu]Lu-PSMA-617. EJNMMI Research 2020, Springer Nature© [57]. Patient C was originally published in Kunikowska et al., [⁶⁸ Ga]Ga-Prostate-Specific Membrane Antigen PET/CT: a novel method for imaging patients with hepatocellular carcinoma. Eur J Nucl Med Mol Imaging, Copyright 2020, Spinger Nature© [99]. Patient D was originally published in Sathekge et al., [⁶⁸ Ga]Ga-PSMA-HBED-CC PET imaging in breast carcinoma patients. Eur J Nucl Med Mol Imaging, 2017, Springer Nature© [122]. These PSMA PET/CT images of four example patients were reprinted from open access articles distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)