Potential Targets Other than PSMA for Prostate Cancer Theranostics: A Systematic Review

Background: Prostate-specific membrane antigen (PSMA) is not sufficiently overexpressed in a small proportion of prostate cancer (PCa) patients, who require other strategies for imaging and/or treatment. We reviewed potential targets other than PSMA for PCa theranostics in nuclear medicine that have already been tested in humans. Methods: We performed a systematic web search in the PubMed and Cochrane databases, with no time restrictions by pooling terms (“prostate cancer”, “prostatic neoplasms”) and (“radioligand”, “radiotracer”). Included articles were clinical studies. The results were synthetized by the target type. Results: We included 38 studies on six different targets: gastrin-releasing peptide receptors (GRPRs) (n = 23), androgen receptor (n = 11), somatostatin receptors (n = 6), urokinase plasminogen activator surface receptor (n = 4), fibroblast activation protein (n = 2 studies) and integrin receptors (n = 1). GRPRs, the most studied target, has a lower expression in high-grade PCa, CRPC and bone metastases. Its use might be of higher interest in treating earlier stages of PCa or low-grade PCa. Radiolabeled fibroblast activation protein inhibitors were the most recent and promising molecules, but specific studies reporting their interest in PCa are needed. Conclusion: Theranostics in nuclear medicine will continue to develop in the future, especially for PCa patients. Targets other than PSMA exist and deserve to be promoted.

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Overcoming stromal barriers to immuno-oncological responses via fibroblast activation protein-targeted therapy

Immunotherapy ◽

10.2217/imt-2020-0066 ◽

2021 ◽

Vol 13 (2) ◽

pp. 155-175

Author(s):

W Nathaniel Brennen ◽

Daniel L J Thorek ◽

Wen Jiang ◽

Timothy E Krueger ◽

Lizamma Antony ◽

...

Keyword(s):

Prostate Cancer ◽

Targeted Therapy ◽

Immune Suppression ◽

Feedback Loop ◽

Wound Repair ◽

Repair Process ◽

Fibroblast Activation Protein ◽

Primary Data ◽

Positive Feedback Loop ◽

Fibroblast Activation

The tumor microenvironment contributes to disease progression through multiple mechanisms, including immune suppression mediated in part by fibroblast activation protein (FAP)-expressing cells. Herein, a review of FAP biology is presented, supplemented with primary data. This includes FAP expression in prostate cancer and activation of latent reservoirs of TGF-β and VEGF to produce a positive feedback loop. This collectively suggests a normal wound repair process subverted during cancer pathophysiology. There has been immense interest in targeting FAP for diagnostic, monitoring and therapeutic purposes. Until recently, this development has outpaced an understanding of the biology; impeding optimal translation into the clinic. A summary of these applications is provided with an emphasis on eliminating tumor-infiltrating FAP-positive cells to overcome stromal barriers to immuno-oncological responses.

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Imaging Fibroblast Activation Protein Alpha Improves Diagnosis of Metastatic Prostate Cancer with Positron Emission Tomography

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-20-1358 ◽

2020 ◽

Vol 26 (18) ◽

pp. 4882-4891 ◽

Cited By ~ 2

Author(s):

Hallie M. Hintz ◽

Joseph P. Gallant ◽

Donald J. Vander Griend ◽

Ilsa M. Coleman ◽

Peter S. Nelson ◽

...

Keyword(s):

Prostate Cancer ◽

Positron Emission Tomography ◽

Metastatic Prostate Cancer ◽

Fibroblast Activation Protein ◽

Emission Tomography ◽

Fibroblast Activation ◽

Positron Emission ◽

Fibroblast Activation Protein Alpha

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High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05423-y ◽

2021 ◽

Author(s):

Claudia Kesch ◽

Leubet Yirga ◽

Katharina Dendl ◽

Analena Handke ◽

Christopher Darr ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Fibroblast Activation Protein ◽

Significant Rise ◽

Androgen Deprivation ◽

Castration Resistant Prostate Cancer ◽

H Index ◽

Fibroblast Activation ◽

Castration Resistant ◽

Pet Ct

Abstract Purpose To evaluate fibroblast-activation-protein (FAP) expression in different clinical stages of prostate cancer (PC) with regards to utility of [68 Ga]Ga-FAPI-04 PET/CT imaging in patients with castration-resistant PC (CRPC). Methods Tissue microarrays (TMAs) were constructed from prostatic tissue from 94 patients at different stages of PC (primary PC, patients undergoing neoadjuvant androgen deprivation therapy, CRPC, and neuroendocrine PC (NEPC)) and were stained with anti-FAP monoclonal antibody. A positive pixel count algorithm (H-Index) was used to compare FAP expression between the groups. Additionally, three men with advanced CRPC or NEPC underwent [68 Ga]Ga-FAPI-04 PET/CT, and PET positivity was analyzed. Results The mean H-index for benign tissue, primary PC, neoadjuvant androgen deprivation therapy before radical prostatectomy, CRPC, and NEPC was 0.018, 0.031, 0.042, 0.076, and 0.051, respectively, indicating a significant rise in FAP expression with advancement of disease. Corroborating these findings [68 Ga]Ga-FAPI-04 PET/CT was highly positive in men with advanced CRPC. Conclusion Increased FAP tissue expression supports the use of FAP inhibitor (FAPI)-molecular theranostics in CRPC.

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Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival

Genes ◽

10.3390/genes13010135 ◽

2022 ◽

Vol 13 (1) ◽

pp. 135

Author(s):

Panagiotis J. Vlachostergios ◽

Athanasios Karathanasis ◽

Vassilios Tzortzis

Keyword(s):

Prostate Cancer ◽

Mrna Expression ◽

Epithelial To Mesenchymal Transition ◽

Fibroblast Activation Protein ◽

Castration Resistant Prostate Cancer ◽

Sequencing Data ◽

Clinical Value ◽

Mesenchymal Transition ◽

Fibroblast Activation ◽

Neuroendocrine Prostate Cancer

Background: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. Methods: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. Results: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). Conclusions: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

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Fibroblast Activation Protein–Targeted PET Imaging of Metastatic Castration-Resistant Prostate Cancer Compared With 68Ga-PSMA and 18F-FDG PET/CT

Clinical Nuclear Medicine ◽

10.1097/rlu.0000000000003837 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Emine Goknur Isik ◽

Duygu Has-Simsek ◽

Oner Sanli ◽

Yasemin Sanli ◽

Serkan Kuyumcu

Keyword(s):

Prostate Cancer ◽

Pet Imaging ◽

Fdg Pet ◽

Fibroblast Activation Protein ◽

Castration Resistant Prostate Cancer ◽

Fibroblast Activation ◽

Castration Resistant ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

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Radioligands Targeting Fibroblast Activation Protein (FAP)

Cancers ◽

10.3390/cancers13225744 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5744

Author(s):

Thomas Lindner ◽

Frederik L. Giesel ◽

Clemens Kratochwil ◽

Sebastian E. Serfling

Keyword(s):

Nuclear Medicine ◽

Fibroblast Activation Protein ◽

Pharmaceutical Companies ◽

Radioligand Therapy ◽

Comprehensive Overview ◽

Fibroblast Activation ◽

Dietary Restrictions ◽

18F Fdg ◽

Medicine Community ◽

Significant Attention

Targeting fibroblast activation protein (FAP) in cancer-associated fibroblasts (CAFs) has attracted significant attention in nuclear medicine. Since these cells are present in most cancerous tissues and FAP is rarely expressed in healthy tissues, anti-FAP tracers have a potential as pan-tumor agents. Compared to the standard tumor tracer [18F]FDG, these tracers show better tumor-to-background ratios (TBR) in many indications. Unlike [18F]FDG, FAP-targeted tracers do not require exhausting preparations, such as dietary restrictions on the part of the patient, and offer the possibility of radioligand therapy (RLT) in a theragnostic approach. Although a radiolabeled antibody was clinically investigated as early as the 1990s, the breakthrough event for FAP-targeting in nuclear medicine was the introduction and clinical application of the so-called FAPI-tracers in 2018. From then, the development and application of FAP-targeted tracers became hot topics for the radiopharmaceutical and nuclear medicine community, and attracted the interest of pharmaceutical companies. The aim of this review is to provide a comprehensive overview of the development of FAP-targeted radiopharmaceuticals and their application in nuclear medicine.

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