Comparison of Prostate-Specific Membrane Antigen Expression Levels in Human Salivary Glands to Non-Human Primates and Rodents.

Background: Prostate-specific membrane antigen (PSMA) has emerged as a promising target for developing radionuclide therapy (RNT) in prostate cancer; however, accumulation of PSMA-RNT in salivary glands can result in irreversible xerostomia. Methods to prevent PSMA-RNT-related xerostomia could be clinically useful; however, little is known about PSMA expression in salivary glands of preclinical animal models. Using [18F]DCFPyL autoradiography/biodistribution, PSMA expression levels were determined in salivary glands of various preclinical monkey and rodent species and compared with humans. Methods: Binding affinities (Kd) and PSMA levels (Bmax) were determined by in vitro [18F]DCFPyL autoradiography studies. In vivo rodent tissue uptakes (%ID/g) were determined from [18F]DCFPyL biodistributions. Results: [18F]DCFPyL exhibited low nanomolar Kd for submandibular gland (SMG) PSMA across all the species. PSMA levels in human SMG (Bmax = 60.91 nM) were approximately two-fold lower compared with baboon SMG but were two- to three-fold higher than SMG PSMA levels of cynomolgus and rhesus. Rodents had the lowest SMG PSMA levels, with the mouse being 10-fold higher than the rat. In vivo rodent biodistribution studies confirmed these results. Conclusions: SMG of monkeys exhibited comparable PSMA expression to human SMG whereas rodents were lower. However, the results suggest that mice are relatively a better small animal preclinical model than rats for PSMA salivary gland studies.

[1]  P. Meyer,et al.  [177Lu]Lu-PSMA-617 Salivary Gland Uptake Characterized by Quantitative In Vitro Autoradiography , 2019, Pharmaceuticals.

[2]  James M. Kelly,et al.  A Single Dose of 225Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model , 2018, The Journal of Nuclear Medicine.

[3]  F. Bruchertseifer,et al.  225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study , 2018, European Journal of Nuclear Medicine and Molecular Imaging.

[4]  N. Filipovic,et al.  In vitro Models and On-Chip Systems: Biomaterial Interaction Studies With Tissues Generated Using Lung Epithelial and Liver Metabolic Cell Lines , 2018, Front. Bioeng. Biotechnol..

[5]  U. Haberkorn,et al.  Initial clinical experience performing sialendoscopy for salivary gland protection in patients undergoing 225Ac-PSMA-617 RLT , 2018, European Journal of Nuclear Medicine and Molecular Imaging.

[6]  W. Cai,et al.  Targeted α-therapy of prostate cancer using radiolabeled PSMA inhibitors: a game changer in nuclear medicine. , 2018, American journal of nuclear medicine and molecular imaging.

[7]  F. Bénard,et al.  Monosodium Glutamate Reduces 68Ga-PSMA-11 Uptake in Salivary Glands and Kidneys in a Preclinical Prostate Cancer Model , 2018, The Journal of Nuclear Medicine.

[8]  G. Krijger,et al.  Impact of external cooling with icepacks on 68Ga-PSMA uptake in salivary glands , 2018, EJNMMI Research.

[9]  R. Baum,et al.  Salivary Gland Toxicity of PSMA Radioligand Therapy: Relevance and Preventive Strategies , 2018, The Journal of Nuclear Medicine.

[10]  Hossein Jadvar,et al.  PSMA Theranostics: Current Status and Future Directions , 2018, Molecular imaging.

[11]  U. Haberkorn,et al.  PSMA-Targeted Radionuclide Therapy and Salivary Gland Toxicity: Why Does It Matter? , 2018, The Journal of Nuclear Medicine.

[12]  L. Smit,et al.  Physiologic distribution of PSMA-ligand in salivary glands and seromucous glands of the head and neck on PET/CT. , 2018, Oral surgery, oral medicine, oral pathology and oral radiology.

[13]  Jolie L. Chang,et al.  Salivary glands regenerate after radiation injury through SOX2‐mediated secretory cell replacement , 2018, EMBO molecular medicine.

[14]  R. Baum,et al.  Injection of Botulinum Toxin for Preventing Salivary Gland Toxicity after PSMA Radioligand Therapy: an Empirical Proof of a Promising Concept , 2018, Nuclear Medicine and Molecular Imaging.

[15]  U. Haberkorn,et al.  Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers , 2017, The Journal of Nuclear Medicine.

[16]  T. Teshima,et al.  Overview of Human Salivary Glands: Highlights of Morphology and Developing Processes , 2017, Anatomical record.

[17]  Devin P. Sullivan,et al.  A subcellular map of the human proteome , 2017, Science.

[18]  P. Choyke,et al.  Fast indirect fluorine-18 labeling of protein/peptide using the useful 6-fluoronicotinic acid-2,3,5,6-tetrafluorophenyl prosthetic group: A method comparable to direct fluorination. , 2017, Journal of labelled compounds & radiopharmaceuticals.

[19]  U. Haberkorn,et al.  PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617 , 2016, The Journal of Nuclear Medicine.

[20]  G. Proctor.  The physiology of salivary secretion. , 2016, Periodontology 2000.

[21]  M. Ogawa,et al.  Functional salivary gland regeneration as the next generation of organ replacement regenerative therapy , 2015, Odontology.

[22]  J. E. Melvin,et al.  Functional Differences in the Acinar Cells of the Murine Major Salivary Glands , 2015, Journal of dental research.

[23]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[24]  A. Villa,et al.  Diagnosis and management of xerostomia and hyposalivation , 2014, Therapeutics and clinical risk management.

[25]  K. Tsubota,et al.  Functional lacrimal gland regeneration by transplantation of a bioengineered organ germ , 2013, Nature Communications.

[26]  T. Tachikawa,et al.  Functional salivary gland regeneration by transplantation of a bioengineered organ germ , 2013, Nature Communications.

[27]  A. Swaroop,et al.  Next-generation sequencing facilitates quantitative analysis of wild-type and Nrl−/− retinal transcriptomes , 2011, Molecular vision.

[28]  C. Contoreggi,et al.  [76Br]BMK‐152, a nonpeptide analogue, with high affinity and low nonspecific binding for the corticotropin‐releasing factor type 1 receptor , 2011, Synapse.

[29]  A. Vissink,et al.  A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact , 2010, Supportive Care in Cancer.

[30]  A. Vissink,et al.  A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life , 2010, Supportive Care in Cancer.

[31]  W. Schultze‐Seemann,et al.  Three conformational antibodies specific for different PSMA epitopes are promising diagnostic and therapeutic tools for prostate cancer , 2009, The Prostate.

[32]  E. Lundberg,et al.  A Genecentric Human Protein Atlas for Expression Profiles Based on Antibodies* , 2008, Molecular & Cellular Proteomics.

[33]  Tiancheng Liu,et al.  Cell‐Surface labeling and internalization by a fluorescent inhibitor of prostate‐specific membrane antigen , 2008, The Prostate.

[34]  Mindy I. Davis,et al.  Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  N. Bander,et al.  Prostate-specific membrane antigen association with filamin A modulates its internalization and NAALADase activity. , 2003, Cancer research.

[36]  D. Bostwick,et al.  Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. , 1998, Urology.

[37]  N. Bander,et al.  Constitutive and antibody-induced internalization of prostate-specific membrane antigen. , 1998, Cancer research.

[38]  D. Bostwick,et al.  Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma , 1998, Cancer.