Статті в журналах: "PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA)"

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Akhtar, Naveed H., Orrin Pail, Ankeeta Saran, Lauren Tyrell, and Scott T. Tagawa. "Prostate-Specific Membrane Antigen-Based Therapeutics." Advances in Urology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/973820.

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Prostate cancer (PC) is the most common noncutaneous malignancy affecting men in the US, leading to significant morbidity and mortality. While significant therapeutic advances have been made, available systemic therapeutic options are lacking. Prostate-specific membrane antigen (PSMA) is a highly-restricted prostate cell-surface antigen that may be targeted. While initial anti-PSMA monoclonal antibodies were suboptimal, the development of monoclonal antibodies such as J591 which are highly specific for the external domain of PSMA has allowed targeting of viable, intact prostate cancer cells. Radiolabeled J591 has demonstrated accurate and selective tumor targeting, safety, and efficacy. Ongoing studies using anti-PSMA radioimmunotherapy with177Lu-J591 seek to improve the therapeutic profile, select optimal candidates with biomarkers, combine with chemotherapy, and prevent or delay the onset of metastatic disease for men with biochemical relapse. Anti-PSMA monoclonal antibody-drug conjugates have also been developed with completed and ongoing early-phase clinical trials. As PSMA is a selective antigen that is highly overexpressed in prostate cancer, anti-PSMA-based immunotherapy has also been studied and utilized in clinical trials.

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Rajasekaran, Ayyappan K., Gopalakrishnapillai Anilkumar, and Jason J. Christiansen. "Is prostate-specific membrane antigen a multifunctional protein?" American Journal of Physiology-Cell Physiology 288, no. 5 (May 2005): C975—C981. http://dx.doi.org/10.1152/ajpcell.00506.2004.

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Prostate-specific membrane antigen (PSMA) is a metallopeptidase expressed predominantly in prostate cancer (PCa) cells. PSMA is considered a biomarker for PCa and is under intense investigation for use as an imaging and therapeutic target. Although the clinical utility of PSMA in the detection and treatment of PCa is evident and is being pursued, very little is known about its basic biological function in PCa cells. The purpose of this review is to highlight the possibility that PSMA might be a multifunctional protein. We suggest that PSMA may function as a receptor internalizing a putative ligand, an enzyme playing a role in nutrient uptake, and a peptidase involved in signal transduction in prostate epithelial cells. Insights into the possible functions of PSMA should improve the diagnostic and therapeutic values of this clinically important molecule.

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Diao, Wei, Huawei Cai, Lihong Chen, Xi Jin, Xinyang Liao, and Zhiyun Jia. "Recent Advances in Prostate-Specific Membrane Antigen-Based Radiopharmaceuticals." Current Topics in Medicinal Chemistry 19, no. 1 (March 26, 2019): 33–56. http://dx.doi.org/10.2174/1568026619666190201100739.

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Background: Prostate cancer (PCa) is the most common sex-related malignancy with high mortality in men worldwide. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of most prostate tumor cells and considered a valuable target for both diagnosis and therapy of prostate cancer. A series of radiolabeled agents have been developed based on the featured PSMA ligands in the previous decade and have demonstrated promising outcomes in clinical research of primary and recurrent PCa. Furthermore, the inspiring response and safety of lutetium-177-PSMA-617 (177Lu-PSMA-617) radiotherapy represent the potential for expanded therapeutic options for metastatic castration-resistant PCa. Retrospective cohort studies have revealed that radiolabeled PSMA agents are the mainstays of the current success, especially in detecting prostate cancer with metastasis and biochemical recurrence. </P><P> Objective: This review is intended to present a comprehensive overview of the current literature on PSMA ligand-based agents for both radionuclide imaging and therapeutic approaches, with a focus on those that have been clinically adopted. </P><P> Conclusion: PSMA-based diagnosis and therapy hold great promise for improving the clinical management of prostate cancer.

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Hong, Jeong Hee. "An Update of Prostate-Specific Membrane Antigen Theranostics in Prostate Cancer." Korean Journal of Urological Oncology 20, no. 4 (November 30, 2022): 207–22. http://dx.doi.org/10.22465/kjuo.2022.20.4.207.

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Theranostics is a new term which involves the integration of therapy and diagnosis in a single platform. Prostate-specific membrane antigen (PSMA) has emerged to be a novel promising target for both diagnostic imaging and therapeutics of prostate cancer. During the past decade, radiotracers targeting the PSMA for positron emission tomography (PET) have been developed. These PET tracers are small molecular inhibitors that bind the extracellular domain of PSMA. With the recent approval of radioisotope labeled PSMA PET for clinical use, the field of PSMA theranostics has come under the spotlight. Can the preliminary efficacy and safety data on PSMA theranostics may change the prostate cancer landscape? In this review, we will focus on the history of development, approval of drug, and diagnostic and therapeutic performance of PSMA PET in patients with prostate cancer.

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Ghosh, Arundhati, Xinning Wang, Eric Klein, and Warren D. W. Heston. "Novel Role of Prostate-Specific Membrane Antigen in Suppressing Prostate Cancer Invasiveness." Cancer Research 65, no. 3 (February 1, 2005): 727–31. http://dx.doi.org/10.1158/0008-5472.727.65.3.

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Abstract Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein, is overexpressed in prostate cancer. PSMA is a unique cell surface marker, negatively regulated by androgen and extensively used for imaging of hormone refractory carcinomas and metastatic foci. PSMA is a carboxypeptidase with two important enzymatic functions, namely, folate hydrolase and NAALADase. PSMA also exhibits an endocytic function, in which it spontaneously recycles through endocytic vesicles. PSMA is overexpressed at various stages of prostate cancer, including androgen-sensitive and -independent disease, increased in expression with early relapse after therapy. We have used in vitro invasion assays to explore the possible role of PSMA in the metastasis of prostate cancer cells. Androgen-dependent prostate cancer lines, which express PSMA endogenously (e.g., LNCaP, MDA PCa2b, and CWR22Rv1) are less invasive compared with androgen-independent PC3 or DU145 cells, neither of which expresses PSMA. Ectopic expression of PSMA in PC3 cells reduced the invasiveness of these cells, suggesting that this reduction in the invasion capability of PSMA-expressing cells is due to PSMA expression and not to intrinsic properties of different prostate cancer cell lines. Furthermore, knockdown of PSMA expression increased invasiveness of LNCaP cells by 5-fold. Finally, expression of PSMA mutants lacking carboxypeptidase activity reduced the impact of PSMA expression on invasiveness. Thus, it seems that the enzymatic activity is associated with the effect of PSMA on invasiveness.

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Vlachostergios, Panagiotis J., Ioannis Zachos, and Vassilios Tzortzis. "Biomarkers in Prostate-Specific Membrane Antigen Theranostics." Diagnostics 11, no. 6 (June 18, 2021): 1108. http://dx.doi.org/10.3390/diagnostics11061108.

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Theranostics of prostate cancer (PC) represents a growing area of development of imaging agents and targeted radionuclide therapeutics against a major target, prostate specific membrane antigen (PSMA). In view of the encouraging efficacy from the use of 177Lu and other radionuclides in metastatic castration-resistant prostate cancer (mCRPC), it is becoming increasingly important to identify surrogate markers that can help predict which patients are more likely to respond and experience improved survival. This review discusses potential predictors of efficacy of PSMA-targeted radionuclide therapies (TRT) segregated in three major categories: imaging, clinical and molecular.

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Plichta, Kristin A., Stephen A. Graves, and John M. Buatti. "Prostate-Specific Membrane Antigen (PSMA) Theranostics for Treatment of Oligometastatic Prostate Cancer." International Journal of Molecular Sciences 22, no. 22 (November 9, 2021): 12095. http://dx.doi.org/10.3390/ijms222212095.

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Theranostics, a combination of therapy and diagnostics, is a field of personalized medicine involving the use of the same or similar radiopharmaceutical agents for the diagnosis and treatment of patients. Prostate-specific membrane antigen (PSMA) is a promising theranostic target for the treatment of prostate cancers. Diagnostic PSMA radiopharmaceuticals are currently used for staging and diagnosis of prostate cancers, and imaging can predict response to therapeutic PSMA radiopharmaceuticals. While mainly used in the setting of metastatic, castrate-resistant disease, clinical trials are investigating the use of PSMA-based therapy at earlier stages, including in hormone-sensitive or hormone-naïve prostate cancers, and in oligometastatic prostate cancers. This review explores the use of PSMA as a theranostic target and investigates the potential use of PSMA in earlier stage disease, including hormone-sensitive metastatic prostate cancer, and oligometastatic prostate cancer.

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Dolgushin, M. B., N. A. Meshcheryakova, A. A. Odzharova, V. B. Matveev, D. I. Nevzorov, O. E. Platonova, and P. V. Kochergin. "18F-PSMA-1007 POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY IN THE DIAGNOSIS OF RECURRENT PROSTATE CANCER: CLINICAL OBSERVATION." Cancer Urology 14, no. 3 (October 2, 2018): 134–38. http://dx.doi.org/10.17650/1726-9776-2018-14-3-134-138.

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Objective: demonstration of possibilities of18F-prostate specific membrane antigen-1007 (18F-PSMA-1007) positron emission tomography/computed tomography (PET/CT) for diagnostic prostate cancer recurrence.The article presents clinical observation of the patient with prostate cancer biochemical recurrence after the multiple treatment.18F-PSMA-1007 PET/CT demonstrates high sensitivity in prostate cancer recurrence diagnostic, in particular with low prostatic specific antigen level.

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Yari, Hooman, Gregory Nkepang, and Vibhudutta Awasthi. "Surface Modification of Liposomes by a Lipopolymer Targeting Prostate Specific Membrane Antigen for Theranostic Delivery in Prostate Cancer." Materials 12, no. 5 (March 5, 2019): 756. http://dx.doi.org/10.3390/ma12050756.

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Prostate specific membrane antigen (PSMA) is a marker for diagnosis and targeted delivery of therapeutics to advanced/metastasized prostate cancer. We report a liposome-based system for theranostic delivery to PSMA-expressing (PSMA+) LNCaP cells. A lipopolymer (P3) comprising of PSMA ligand (PSMAL), polyethylene glycol (PEG2000), and palmitate was synthesized and post-inserted into the surface of preformed liposomes. These P3-liposomes were loaded with doxorubicin and radiolabeled with 99mTc radionuclide to study their theranostic characteristics. Differential expression of PSMA on LNCaP and PC3 cells was confirmed by immunoblotting as well as by uptake of PSMAL labeled with 18F radionuclide. We found that the uptake of 99mTc-labeled P3-liposomes by LNCaP cells was >3-fold higher than 99mTc-labeled Plain-liposomes; the amount of doxorubicin delivered to LNCaP cells was also found to be >3-fold higher by P3-liposomes. Cell-based cytotoxicity assay results showed that doxorubicin-loaded P3-liposomes were significantly more toxic to LNCaP cells (p < 0.05), but not to PSMA-negative PC3 cells. Compared to doxorubicin-loaded Plain-liposomes, the IC50 value of doxorubicin-loaded P3-liposomes was reduced by ~5-fold in LNCaP cells. Together, these results suggest that surface functionalization of liposomes with small PSMA-binding motifs, such as PSMAL, can provide a viable platform for specific delivery of theranostics to PSMA+ prostate cancer.

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Giraudet, Anne-Laure, David Kryza, Michael Hofman, Aurélie Moreau, Karim Fizazi, Aude Flechon, Rodney J. Hicks, and Ben Tran. "PSMA targeting in metastatic castration-resistant prostate cancer: where are we and where are we going?" Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110538. http://dx.doi.org/10.1177/17588359211053898.

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Prostate-specific membrane antigen (PSMA) is highly expressed on the membrane of most prostate cancer cells and to a lesser extent in normal tissues. Many vectors targeting this protein have been created over the past decade and numerous clinical studies have positively demonstrated the tolerance and efficacy of radiolabeled prostate-specific membrane antigen ligands for PSMA radioligand therapy (PRLT). Preliminary results are encouraging that PRLT will become an important addition to the current therapeutic options in a number of settings. Improvement in radiopharmaceutical targeting and combination with other oncological agents are under investigation to further improve its therapeutic efficacy. These encouraging results have led to the development of other therapies using PSMA as a target, such as PSMA–targeted chimeric antigen receptor T-cells, PSMA–targeted antibody drug conjugates, and PSMA–targeted bi-specific T-cell-directed therapy. This narrative review details the current state and advancements in prostate-specific membrane antigen targeting in prostate cancer treatment.

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Unger, Clara, Peter Bronsert, Kerstin Michalski, Anna Bicker, and Ingolf Juhasz-Böss. "Expression of Prostate Specific Membrane Antigen (PSMA) in Breast Cancer." Geburtshilfe und Frauenheilkunde 82, no. 01 (January 2022): 50–58. http://dx.doi.org/10.1055/a-1638-9429.

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Abstract Background Prostate specific membrane antigen (PSMA) is a promising protein for breast cancer patients. It has not only been detected in prostate cancer but is also expressed by tumor cells and the endothelial cells of tumor vessels in breast cancer patients. PSMA plays a role in tumor progression and tumor angiogenesis. For this reason, a number of diagnostic and therapeutic methods to target PSMA have been developed. Method This paper provides a general structured overview of PSMA and its oncogenic potential, with a special focus on its role in breast cancer. This narrative review is based on a selective literature search carried out in PubMed and the library of Freiburg University Clinical Center. The following key words were used for the search: “PSMA”, “PSMA and breast cancer”, “PSMA PET/CT”, “PSMA tumor progression”. Relevant articles were explicitly read through, processed, and summarized. Conclusion PSMA could be a new diagnostic and therapeutic alternative, particularly for triple-negative breast cancer. It appears to be a potential predictive and prognostic marker.

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Castelletti, Deborah, Marwan Alfalah, Martin Heine, Zeynep Hein, Ruth Schmitte, Giulio Fracasso, Marco Colombatti, and Hassan Y. Naim. "Different glycoforms of prostate-specific membrane antigen are intracellularly transported through their association with distinct detergent-resistant membranes." Biochemical Journal 409, no. 1 (December 11, 2007): 149–57. http://dx.doi.org/10.1042/bj20070396.

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Hormone-refractory prostate carcinomas as well as the neovasculature of different tumours express high levels of PSMA (prostate-specific membrane antigen). PSMA is a type II-transmembrane glycoprotein and a potential tumour marker for both diagnosis and passive immunotherapy. Here, we report on the association of PSMA with DRMs (detergent-resistant membranes) at different stages of the protein maturation pathway in human prostate carcinoma LNCaP cells. At least three PSMA glycoforms were biochemically identified based on their extractability behaviour in different non-ionic detergents. In particular, one precursor glycoform of PSMA is associated with Tween 20-insoluble DRMs, whereas the complex glycosylated protein segregates into membrane structures that are insoluble in Lubrol WX and display a different lipid composition. Association of PSMA with these membranes occurs in the Golgi compartment together with the acquisition of a native conformation. PSMA homodimers reach the plasma membrane of LNCaP cells in Lubrol WX-insoluble lipid/protein complexes. At the steady state, the majority of PSMA remains within these membrane microdomains at the cell surface. We conclude that the intracellular transport of PSMA occurs through populations of DRMs distinct for each biosynthetic form and cellular compartment.

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Conway, Rebecca E., Nenad Petrovic, Zhong Li, Warren Heston, Dianqing Wu, and Linda H. Shapiro. "Prostate-Specific Membrane Antigen Regulates Angiogenesis by Modulating Integrin Signal Transduction." Molecular and Cellular Biology 26, no. 14 (July 15, 2006): 5310–24. http://dx.doi.org/10.1128/mcb.00084-06.

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ABSTRACT The transmembrane peptidase prostate-specific membrane antigen (PSMA) is universally upregulated in the vasculature of solid tumors, but its functional role in tumor angiogenesis has not been investigated. Here we show that angiogenesis is severely impaired in PSMA-null animals and that this angiogenic defect occurs at the level of endothelial cell invasion through the extracellular matrix barrier. Because proteolytic degradation of the extracellular matrix is a critical component of endothelial invasion in angiogenesis, it is logical to assume that PSMA participates in matrix degradation. However, we demonstrate a novel and more complex role for PSMA in angiogenesis, where it is a principal component of a regulatory loop that is tightly modulating laminin-specific integrin signaling and GTPase-dependent, p21-activated kinase 1 (PAK-1) activity. We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis. Interestingly, the neutralization of β1 or the inactivation of PAK increases PSMA activity, suggesting that they negatively regulate PSMA. This negative regulation is mediated by the cytoskeleton as the disruption of interactions between the PSMA cytoplasmic tail and the anchor protein filamin A decreases PSMA activity, integrin function, and PAK activation. Finally, the inhibition of PAK activation enhances the PSMA/filamin A interaction and, thus, boosts PSMA activity. These data imply that PSMA participates in an autoregulatory loop, wherein active PSMA facilitates integrin signaling and PAK activation, leading to both productive invasion and downregulation of integrin β1 signaling via reduced PSMA activity. Therefore, we have identified a novel role for PSMA as a true molecular interface, integrating both extracellular and intracellular signals during angiogenesis.

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Wang, Xinning, Aditi Shirke, Ethan Walker, Rongcan Sun, Gopolakrishnan Ramamurthy, Jing Wang, Lingpeng Shan, et al. "Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer." Cancers 13, no. 3 (January 22, 2021): 417. http://dx.doi.org/10.3390/cancers13030417.

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Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand–drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule–drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body–drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.

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Sommer, Ulrich, Tiziana Siciliano, Celina Ebersbach, Alicia-Marie K. Beier, Matthias B. Stope, Korinna Jöhrens, Gustavo B. Baretton, Angelika Borkowetz, Christian Thomas, and Holger H. H. Erb. "Impact of Androgen Receptor Activity on Prostate-Specific Membrane Antigen Expression in Prostate Cancer Cells." International Journal of Molecular Sciences 23, no. 3 (January 18, 2022): 1046. http://dx.doi.org/10.3390/ijms23031046.

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Prostate-specific membrane antigen (PSMA) is an essential molecular regulator of prostate cancer (PCa) progression coded by the FOLH1 gene. The PSMA protein has become an important factor in metastatic PCa diagnosis and radioligand therapy. However, low PSMA expression is suggested to be a resistance mechanism to PSMA-based imaging and therapy. Clinical studies revealed that androgen receptor (AR) inhibition increases PSMA expression. The mechanism has not yet been elucidated. Therefore, this study investigated the effect of activation and inhibition of androgen signaling on PSMA expression levels in vitro and compared these findings with PSMA levels in PCa patients receiving systemic therapy. To this end, LAPC4, LNCaP, and C4-2 PCa cells were treated with various concentrations of the synthetic androgen R1881 and antiandrogens. Changes in FOLH1 mRNA were determined using qPCR. Open access databases were used for ChIP-Seq and tissue expression analysis. Changes in PSMA protein were determined using western blot. For PSMA staining in patients’ specimens, immunohistochemistry (IHC) was performed. Results revealed that treatment with the synthetic androgen R1881 led to decreased FOLH1 mRNA and PSMA protein. This effect was partially reversed by antiandrogen treatment. However, AR ChIP-Seq analysis revealed no canonical AR binding sites in the regulatory elements of the FOLH1 gene. IHC analysis indicated that androgen deprivation only resulted in increased PSMA expression in patients with low PSMA levels. The data demonstrate that AR activation and inhibition affects PSMA protein levels via a possible non-canonical mechanism. Moreover, analysis of PCa tissue reveals that low PSMA expression rates may be mandatory to increase PSMA by androgen deprivation.

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Zare, Hamed, Masoumeh Rajabibazl, Iraj Rasooli, Walead Ebrahimizadeh, Hamid Bakherad, Leila Safaiee Ardakani, and Seyed Latif Mousavi Gargari. "Production of Nanobodies against Prostate-Specific Membrane Antigen (PSMA) Recognizing LnCaP Cells." International Journal of Biological Markers 29, no. 2 (April 2014): 169–79. http://dx.doi.org/10.5301/jbm.5000063.

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Prostate cancer is the most common type of cancer in men. The antibody-mediated therapy for cancer treatment depends on the identification of selected molecular targets. The prostate-specific membrane antigen (PSMA) is a potential molecular target in prostate cancer and is abundantly expressed in this type of cancer. This study is aimed at designing and producing a recombinant PSMA epitope and a monoclonal nanobody with a high affinity toward the PSMA protein. A DNA fragment encoding the dominant epitopes of PSMA was designed, synthesized, and expressed in E. coli BL21 (DE3). A camel was immunized with the purified recombinant PSMA (rPSMA). Following mRNA isolation and cDNA synthesis, the variable fragment of heavy-chain antibodies (VHH) fragments were cloned and displayed on the surface of an M13 phage and used in sequential panning rounds. After phage ELISA and selection of colonies with the highest affinity, soluble nanobodies were produced and evaluated. Affinity of the nanobodies to rPSMA was estimated to be 3.5 × 10−7. Adherence of the purified anti-PSMA VHH was tested in cell-ELISA in the LnCaP and PC3 cell lines. VHH efficiently bound to LnCaP cells. The high specificity and affinity of this nanobody suggests its possible application as an effective tool in the diagnosis and treatment of prostate cancer.

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Inubushi, Masayuki, Hiroyuki Miura, Ichiei Kuji, Kimiteru Ito, and Ryogo Minamimoto. "Current status of radioligand therapy and positron-emission tomography with prostate-specific membrane antigen." Annals of Nuclear Medicine 34, no. 12 (November 11, 2020): 879–83. http://dx.doi.org/10.1007/s12149-020-01549-5.

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AbstractProstate-specific membrane antigen (PSMA) is a transmembrane glycoprotein highly expressed by prostate cancer cells. PSMA-based radioligand therapy (RLT) emerged as a promising therapeutic option for prostate cancer in the early 2000s, and has been clinically validated with great enthusiasm during these past two decades. Last year, the European Association of Nuclear Medicine (EANM) published the procedure guidelines for the safe clinical practice of Lutetium-177 (177Lu)-labelled PSMA RLT. In addition, PSMA RLT with alpha-ray-emitting radioisotopes has been also developed recently. Following the clinical use of 177Lu-PSMA RLT, PSMA-targeted positron-emission tomography (PET) with Gallium-68 (68Ga) has been performed inevitably for “theranostics” for the last decade; prostate cancer is going to be treated with PSMA-RLT based on the diagnosis by PSMA-PET. Furthermore, the diagnostic usefulness of 68Ga-PSMA PET has been documented in various diseases beyond prostate cancer more recently. Regrettably, Japan is behind European countries and the United States in this field, and has just made a belated start of their clinical trials. In this review article, we briefly overviewed the current status of PSMA RLT and PSMA PET. We hope that this topic will be a particular focus of attention for most ANM readers in Japan, and that our efforts will help to facilitate the early approval of PSMA RLT and PSMA PET by the Japanese government even if only slightly.

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Lozinski, Mathew, Michael Fay, Nikola Bowden, Moira Graves, and Paul Tooney. "TMIC-41. PROSTATE SPECIFIC MEMBRANE ANTIGEN EXPRESSION IN PRIMARY AND RECURRENT GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi256. http://dx.doi.org/10.1093/neuonc/noz175.1075.

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Abstract Patients with glioblastoma almost always suffer a recurrence of an aggressive treatment resistant tumour and succumb within months highlighting the need to develop treatment options for recurrent glioblastoma. One potential target is prostate specific membrane antigen (PSMA) expressed on the new vessels in primary glioblastoma tumours. This study compared the expression of PSMA in primary and recurrent glioblastoma tumours. Formalin-fixed paraffin-embedded sections of primary and matched recurrent tumours from 13 patients with glioblastoma were processed for PSMA immunohistochemical labelling. PSMA expression was scored from digitally scanned sections using a categorical system (Total PSMA expression = PSMA label intensity (0–3) x percent PSMA-positive blood vessels). Little PSMA labelling was observed in any adjacent ‘unaffected’ brain tissue. PSMA was localised to blood vessels including those displaying microvascular proliferation in 12/13 primary and 9/13 recurrent glioblastoma tumours. Total PSMA expression scores ranged from 0 – 230 (maximum score = 300) and was divided into low and high expression based on a median split (median = 57) of PSMA expression across all tumours. Regression analysis showed a significant difference in PSMA expression between primary and recurrent glioblastoma (p = 0.04) with PSMA being highly expressed in ~70% of primary and only 31% of recurrent glioblastoma. Three cases displayed high expression in both primary and recurrent glioblastoma and one case had no PSMA expression at all. In conclusion, whilst higher expression of PSMA was detected in more primary tumours, 70%+ of all primary and recurrent tumours expressed PSMA to some extent adding evidence that this may be a useful target for treatment of glioblastoma. Larger cohorts and other techniques for detecting PSMA are needed to provide further evidence for PSMA’s utility as a target and to further define which glioblastoma patients are most likely to benefit from this approach.

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Tateishi, Ukihide. "Prostate-specific membrane antigen (PSMA)–ligand positron emission tomography and radioligand therapy (RLT) of prostate cancer." Japanese Journal of Clinical Oncology 50, no. 4 (March 9, 2020): 349–56. http://dx.doi.org/10.1093/jjco/hyaa004.

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Abstract From a clinical perspective, prostate-specific membrane antigen (PSMA) is a valuable target for both diagnosis and radioligand therapy (RLT) of prostate cancer. The term ‘specific’ has been used to characterize a histologic hallmark of overexpression in the membrane of most prostate cancer. Many PSMA ligands have been developed since the previous decade and have been used in several clinical trials and clinical studies. However, procedure, specification, protocol, interpretation criteria, radiation dose, and cost-effectiveness of PSMA ligands have not been fully explained. Regardless of worldwide use of promising PSMA-ligand PET and RLT, it has not been approved in Japan. Expedited introduction of PSMA-ligand PET and RLT to Japan and implementation of clinical study are eager for many patients with prostate cancer.

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Lupold, Shawn E., and Ronald Rodriguez. "Disulfide-constrained peptides that bind to the extracellular portion of the prostate-specific membrane antigen." Molecular Cancer Therapeutics 3, no. 5 (May 1, 2004): 597–603. http://dx.doi.org/10.1158/1535-7163.597.3.5.

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Abstract The prostate-specific membrane antigen (PSMA) is a well-characterized surface antigen, overexpressed in the most advanced, androgen-resistant human prostate cancer cells. We sought to exploit PSMA cell surface properties as a target for short peptides that will potentially guide protein-based therapeutics, such as viral vectors, to prostate cancer cells. Two separate phage display peptide strategies were applied, in parallel, to purified PSMA protein bound to two separate substrates. We reasoned that peptide sequences common to both substrate selections would be specific binders of PSMA. Additionally, the design allowed for stringent cross-selections, where phage populations from one selection condition could be applied to the alternative substrate. These strategies resulted in a series of phage displayed peptides able to bind to PSMA by ELISA and direct binding assays, both with purified protein and in prostate cancer cells. Cell binding is competitively inhibited by purified PSMA. The synthesized peptides are capable of enhancing PSMA carboxypeptidase enzymatic activity, suggesting protein folding stabilization. The discovery of these peptides provides the foundation for subsequent development of peptide targeted therapeutics against prostate cancer.

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Luo, Dong, Xinning Wang, Sophia Zeng, Gopalakrishnan Ramamurthy, Clemens Burda, and James P. Basilion. "Prostate-specific membrane antigen targeted gold nanoparticles for prostate cancer radiotherapy: does size matter for targeted particles?" Chemical Science 10, no. 35 (2019): 8119–28. http://dx.doi.org/10.1039/c9sc02290b.

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Prostate-Specific Membrane Antigen (PSMA) targeted radiosensitizers are developed for prostate cancer CT imaging and radiotherapy based on gold nanoparticles and a high-affinity targeting peptide, PSMA-1, revealing a size-dependent pattern.

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Nikfarjam, Zahra, Farshid Zargari, Alireza Nowroozi, and Omid Bavi. "Metamorphosis of prostate specific membrane antigen (PSMA) inhibitors." Biophysical Reviews 14, no. 1 (January 13, 2022): 303–15. http://dx.doi.org/10.1007/s12551-021-00919-1.

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Tishchenko, Viktoriia K., Vasily M. Petriev, Oksana P. Vlasova, Andrei A. Pankratov, Natalia B. Morozova, Petr V. Shegai, Sergei A. Ivanov, and Andrei D. Kaprin. "99mTc-Labelled Low Molecular Weight Inhibitors of Prostate-Specific Membrane Antigen." Annals of the Russian academy of medical sciences 77, no. 6 (February 4, 2023): 420–36. http://dx.doi.org/10.15690/vramn2207.

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High morbidity and mortality rates of prostate cancer (PCa) determine the requirement of looking for new methods of its early diagnosis. Methods of nuclear medicine have a special place in addressing this problem as they allow functional, metabolic and other processes imaging in body, which occur during the cancer development. This approach supposes the use of radiopharmaceuticals (RP), which are capable of selective binding to a specific biological target, for example, prostate-specific membrane antigen (PSMA), which is known to be overexpressed in PCa. Current development of new radiotracers for PCa imaging is focused on low molecular weight PSMA inhibitors due to their high specific binding to PSMA and rapid urinary excretion. Technetium-99m remains the appropriate radionuclide for diagnostic studies due to its optimal nuclear properties, ease of production and versatile coordination chemistry. Therefore, single-photon emission computed tomography (SPECT) imaging with 99mTc-PSMA radioligands can be a cost effective alternative to PET with 68Ga- or 18F-labeled RP. The aim of this review is to summarize and analyze currently available data on 99mTc-labeled low molecular weight PSMA inhibitors for metastatic PCa imaging.

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Kaittanis, Charalambos, Chrysafis Andreou, Haley Hieronymus, Ninghui Mao, Catherine A. Foss, Matthias Eiber, Gregor Weirich, et al. "Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors." Journal of Experimental Medicine 215, no. 1 (November 15, 2017): 159–75. http://dx.doi.org/10.1084/jem.20171052.

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Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein–coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA’s carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I. Activated mGluR I subsequently induces activation of phosphoinositide 3-kinase (PI3K) through phosphorylation of p110β independent of PTEN loss. The p110β isoform of PI3K plays a particularly important role in the pathogenesis of prostate cancer, but the origin of its activation was so far unknown. PSMA expression correlated with PI3K–Akt signaling in cells, animal models, and patients. We interrogated the activity of the PSMA–PI3K axis through positron emission tomography and magnetic resonance imaging. Inhibition of PSMA in preclinical models inhibited PI3K signaling and promoted tumor regression. Our data present a novel oncogenic signaling role of PSMA that can be exploited for therapy and interrogated with imaging.

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Lauri, Chiara, Lorenzo Chiurchioni, Vincenzo Marcello Russo, Luca Zannini, and Alberto Signore. "PSMA Expression in Solid Tumors beyond the Prostate Gland: Ready for Theranostic Applications?" Journal of Clinical Medicine 11, no. 21 (November 7, 2022): 6590. http://dx.doi.org/10.3390/jcm11216590.

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In the past decades, the expanding use of prostate-specific membrane antigen (PSMA) imaging for prostate cancer has led to the incidental detection of a lot of extra-prostatic malignancies showing an increased uptake of PSMA. Due to these incidental findings, the increasing amount of immunohistochemistry studies and the deeper knowledge of the mechanisms of expression of this antigen, it is now clear that “PSMA” is a misnomer, since it is not specific to the prostate gland. Nevertheless, this lack of specificity could represent an interesting opportunity to bring new insights on the biology of PSMA and its sites of expression to image and treat new conditions, particularly several cancers. In this review, we will describe the main extra-prostatic cancers that exhibit PSMA expression and that can be studied with PSMA-based positron emission tomography–computed tomography (PET/CT) as an additional or alternative tool to conventional imaging. In particular, we will focus on cancers in which a radioligand therapy with 177lutetium has been attempted, aiming to provide an overview of the possible future theragnostic applications of PSMA.

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Kessel, Katharina, Christof Bernemann, Martin Bögemann, and Kambiz Rahbar. "Evolving Castration Resistance and Prostate Specific Membrane Antigen Expression: Implications for Patient Management." Cancers 13, no. 14 (July 16, 2021): 3556. http://dx.doi.org/10.3390/cancers13143556.

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Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease, despite multiple novel treatment options. The role of prostate-specific membrane antigen (PSMA) in the process of mCRPC development has long been underestimated. During the last years, a new understanding of the underlying molecular mechanisms of rising PSMA expression and its association with disease progression has emerged. Accurate understanding of these complex interactions is indispensable for a precise diagnostic process and ultimately successful treatment of advanced prostate cancer. The combination of different novel therapeutics such as androgen deprivation agents, 177LU-PSMA radioligand therapy and PARP inhibitors promises a new kind of efficacy. In this review, we summarize the current knowledge about the most relevant molecular mechanisms around PSMA in mCRPC development and how they can be implemented in mCRPC management.

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O'Keefe, Denise S., Dean J. Bacich, and Warren D. W. Heston. "Comparative analysis of prostate-specific membrane antigen (PSMA) versus a prostate-specific membrane antigen-like gene." Prostate 58, no. 2 (February 1, 2004): 200–210. http://dx.doi.org/10.1002/pros.10319.

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Ptacek, Jakub, Dong Zhang, Liming Qiu, Sven Kruspe, Lucia Motlova, Petr Kolenko, Zora Novakova, et al. "Structural basis of prostate-specific membrane antigen recognition by the A9g RNA aptamer." Nucleic Acids Research 48, no. 19 (June 11, 2020): 11130–45. http://dx.doi.org/10.1093/nar/gkaa494.

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Abstract Prostate-specific membrane antigen (PSMA) is a well-characterized tumor marker associated with prostate cancer and neovasculature of most solid tumors. PSMA-specific ligands are thus being developed to deliver imaging or therapeutic agents to cancer cells. Here, we report on a crystal structure of human PSMA in complex with A9g, a 43-bp PSMA-specific RNA aptamer, that was determined to the 2.2 Å resolution limit. The analysis of the PSMA/aptamer interface allows for identification of key interactions critical for nanomolar binding affinity and high selectivity of A9g for human PSMA. Combined with in silico modeling, site-directed mutagenesis, inhibition experiments and cell-based assays, the structure also provides an insight into structural changes of the aptamer and PSMA upon complex formation, mechanistic explanation for inhibition of the PSMA enzymatic activity by A9g as well as its ligand-selective competition with small molecules targeting the internal pocket of the enzyme. Additionally, comparison with published protein–RNA aptamer structures pointed toward more general features governing protein-aptamer interactions. Finally, our findings can be exploited for the structure-assisted design of future A9g-based derivatives with improved binding and stability characteristics.

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Stopa, Brittany M., James Crowley, Csaba Juhász, Cara M. Rogers, Mark R. Witcher, and Jackson W. Kiser. "Prostate-Specific Membrane Antigen as Target for Neuroimaging of Central Nervous System Tumors." Molecular Imaging 2022 (April 15, 2022): 1–23. http://dx.doi.org/10.1155/2022/5358545.

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Introduction. Positron emission tomography (PET) imaging with prostate-specific membrane antigen- (PSMA-) binding tracers has been found incidentally to demonstrate uptake in CNS tumors. Following the encouraging findings of several such case reports, there is a growing interest in the potential application of PSMA-targeted PET imaging for diagnostics, theranostics, and monitoring of CNS tumors. This is a systematic literature review on PSMA-binding tracers in CNS tumors. Methods. A PubMed search was conducted, including preclinical and clinical reports. One hundred and twelve records were identified, and after screening, 56 were included in the final report. Results. Tissue studies demonstrated PSMA expression in tumor vascular endothelial cells, without expression in normal brain tissue, though the extent and intensity of staining varied by anti-PSMA antibody and methodology. Most included studies reported on gliomas, which showed strong PSMA ligand uptake and more favorable tumor to background ratios than other PET tracers. There are also case reports demonstrating PSMA ligand uptake in prostate cancer brain metastases, nonprostate cancer brain metastases, and meningiomas. We also review the properties of the various PSMA-binding radiotracers available. Therapeutic and theranostic applications of PSMA-binding tracers have been studied, including labeled alpha- and beta-ray emitting isotopes, as well as PSMA targeting in directing MRI-guided focused ultrasound. Conclusions. There is a potential application for PSMA-targeted PET in neuro-oncology as a combination of diagnostic and therapeutic use, as a theranostic modality for managing CNS tumors. Further research is needed regarding the mechanism(s) of PSMA expression in CNS tumors and its differential performance by tumor type.

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Feneley, MR, H. Jan, M. Granowska, SJ Mather, D. Ellison, J. Glass, M. Coptcoat, et al. "Imaging with prostate-specific membrane antigen (PSMA) in prostate cancer." Prostate Cancer and Prostatic Diseases 3, no. 1 (May 10, 2000): 47–52. http://dx.doi.org/10.1038/sj.pcan.4500390.

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Lee, Florence, Angela Yu, Amanda Anderson, Dena Marrinucci, Wells W. Magargal, Vincent A. DiPippo, and William C. Olson. "Expression of prostate-specific membrane antigen (PSMA) on circulating tumor cells (CTCs) in castration-resistant prostate cancer." Journal of Clinical Oncology 32, no. 4_suppl (February 1, 2014): 266. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.266.

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266 Background: Prostate-specific membrane antigen (PSMA) is expressed ubiquitously in prostate adenocarcinoma, and the intensity of expression increases with disease aggressiveness. Exploiting PSMA for therapy could potentially be aided by a minimally invasive means for measuring PSMA on tumor cells. Here we describe the development and characteristics of a novel assay for quantitating PSMA on canonical and non-canonical circulating tumor cells (CTCs). Methods: The PSMA CTC test was developed using LNCaP (high PSMA), 22Rv1 (low PSMA) and PC3 (no PSMA) cells spiked into normal blood. Nucleated blood cells were plated onto glass slides and subjected to immunofluorescent staining followed by CTC identification using the Pyxis Scanning Platform at Epic Sciences. The four-color assay evaluated PSMA expression on individual CTCs, identified as cells which are cytokeratin+, CD45-, and with an intact DAPI nucleus. Multiple antibody clones and assay conditions were evaluated, and the final PSMA CTC test has high specificity and sensitivity. Acceptance criteria included signal intensities in LNCaP versus PC3, subcellular localization of PSMA, and potential interference by a PSMA-targeted therapy. Clinical feasibility of the optimized assay was assessed on samples from CRPC patients. Results: The average PSMA signal intensity for LNCaP was 20-fold higher than that for PC3 and 10-fold higher than the minimum cutoff. PSMA displayed a predominantly membrane-localized pattern of staining that was distinct from cytokeratin. Assay performance was unaffected by the presence of PSMA ADC, a PSMA-targeted antibody-drug conjugate that is in phase II clinical testing. In feasibility tests on patient samples, the assay demonstrated utility in detecting and quantitating PSMA on individual and clustered CTCs as well as on apoptotic, cytokeratin-negative, and small cytokeratin-positive CTC candidates. Conclusions: PSMA expression was successfully detected and quantitated on diverse types of circulating cells present in the blood of patients with CRPC. Assay performance was unaffected by the presence of a PSMA-targeted therapeutic agent. PSMA CTC data are being collected in the ongoing phase II study of PSMA ADC for comparison with treatment outcomes.

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Rajasekaran, Sigrid A., Gopalakrishnapillai Anilkumar, Eri Oshima, James U. Bowie, He Liu, Warren Heston, Neil H. Bander, and Ayyappan K. Rajasekaran. "A Novel Cytoplasmic Tail MXXXL Motif Mediates the Internalization of Prostate-specific Membrane Antigen." Molecular Biology of the Cell 14, no. 12 (December 2003): 4835–45. http://dx.doi.org/10.1091/mbc.e02-11-0731.

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Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed at high levels in prostate cancer and in tumor-associated neovasculature. In this study, we report that PSMA is internalized via a clathrin-dependent endocytic mechanism and that internalization of PSMA is mediated by the five N-terminal amino acids (MWNLL) present in its cytoplasmic tail. Deletion of the cytoplasmic tail abolished PSMA internalization. Mutagenesis of N-terminal amino acid residues at position 2, 3, or 4 to alanine did not affect internalization of PSMA, whereas mutation of amino acid residues 1 or 5 to alanine strongly inhibited internalization. Using a chimeric protein composed of Tac antigen, the α-chain of interleukin 2-receptor, fused to the first five amino acids of PSMA (Tac-MWNLL), we found that this sequence is sufficient for PSMA internalization. In addition, inclusion of additional alanines into the MWNLL sequence either in the Tac chimera or the full-length PSMA strongly inhibited internalization. From these results, we suggest that a novel MXXXL motif in the cytoplasmic tail mediates PSMA internalization. We also show that dominant negative μ2 of the adaptor protein (AP)-2 complex strongly inhibits the internalization of PSMA, indicating that AP-2 is involved in the internalization of PSMA mediated by the MXXXL motif.

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Shukla, Sourabh, Isaac Marks, Derek Church, Soo-Khim Chan, Jonathan K. Pokorski, and Nicole F. Steinmetz. "Tobacco mosaic virus for the targeted delivery of drugs to cells expressing prostate-specific membrane antigen." RSC Advances 11, no. 33 (2021): 20101–8. http://dx.doi.org/10.1039/d1ra03166j.

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Prostate-specific membrane antigen (PSMA) is a membrane-bound protein that is preferentially expressed in the prostate gland and induced in many prostate cancers, making it an important target for new diagnostics and therapeutics.

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Machulkin, Aleksei E., Ekaterina A. Nimenko, Nikolay U. Zyk, Anastasiia A. Uspenskaia, Galina B. Smirnova, Irina I. Khan, Vadim S. Pokrovsky, et al. "Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate." Molecules 27, no. 24 (December 12, 2022): 8795. http://dx.doi.org/10.3390/molecules27248795.

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Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.

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Dorff, Tanya B., Stefano Fanti, Andrea Farolfi, Robert E. Reiter, Taylor Y. Sadun, and Oliver Sartor. "The Evolving Role of Prostate-Specific Membrane Antigen–Based Diagnostics and Therapeutics in Prostate Cancer." American Society of Clinical Oncology Educational Book, no. 39 (May 2019): 321–30. http://dx.doi.org/10.1200/edbk_239187.

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Prostate-specific membrane antigen (PSMA)–based imaging seeks to fill some critical gaps in prostate cancer staging and response assessment, and may select patients for treatment with radiolabeled PSMA conjugates. In biochemical recurrence, at prostate-specific antigen (PSA) levels as low as 0.2 ng/dL, 68Ga-PSMA imaging has demonstrated a 42% detection rate of occult metastatic disease, and detection has been greater than 95% when PSA levels are higher than 2 ng/dL. This may facilitate novel approaches, including salvage lymphadenectomy or metastasis-directed radiation therapy, in patients with oligometastatic disease. PSMA-based imaging has shown promise in evaluating treatment response in hormone-sensitive and castration-resistant disease; however, additional longitudinal assessment is needed given the heterogeneity in uptake changes after the initiation of androgen-deprivation therapy. Changes in uptake must be taken in context of RECIST measurements and other response parameters, given the potential for growth of PSMA-negative lesions and persistent uptake in treated bone lesions of uncertain significance. For selecting patients to receive PSMA-targeted radioconjugate therapy, standardized uptake value thresholds remain to be established. Nevertheless, preliminary data from 177Lu-PSMA theranostic trials have yielded PSA responses in up to 57% of patients, as well as pain relief and improved quality of life. Thrombocytopenia was the most common grade 3 or greater toxicity; however, grade 1 xerostomia occurred frequently and was cited as the most common reason for treatment discontinuation.

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Vannini, Andrea, Federico Parenti, Daniela Bressanin, Catia Barboni, Anna Zaghini, Gabriella Campadelli-Fiume, and Tatiana Gianni. "Towards a Precision Medicine Approach and In Situ Vaccination against Prostate Cancer by PSMA-Retargeted oHSV." Viruses 13, no. 10 (October 16, 2021): 2085. http://dx.doi.org/10.3390/v13102085.

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Prostate specific membrane antigen (PSMA) is a specific high frequency cell surface marker of prostate cancers. Theranostic approaches targeting PSMA show no major adverse effects and rule out off-tumor toxicity. A PSMA-retargeted oHSV (R-405) was generated which both infected and was cytotoxic exclusively for PSMA-positive cells, including human prostate cancer LNCaP and 22Rv1 cells, and spared PSMA-negative cells. R-405 in vivo efficacy against LLC1-PSMA and Renca-PSMA tumors consisted of inhibiting primary tumor growth, establishing long-term T immune response, immune heating of the microenvironment, de-repression of the anti-tumor immune phenotype, and sensitization to checkpoint blockade. The in situ vaccination protected from distant challenge tumors, both PSMA-positive and PSMA-negative, implying that it was addressed also to LLC1 tumor antigens. PSMA-retargeted oHSVs are a precision medicine tool worth being additionally investigated in the immunotherapeutic and in situ vaccination landscape against prostate cancers.

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Hupe, Marie C., Christian Philippi, Doris Roth, Christiane Kuempers, Julika Ribbat-Idel, Finn Becker, Vincent Joerg, et al. "Using PSMA (prostate-specific membrane antigen) evaluation on prostate biopsies for risk stratification at time of initial diagnosis." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 6. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.6.

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6 Background: Stratifying prostate cancer (PCa) patients into risk groups at time of initial diagnosis for individual treatment decision is still a major clinical challenge. PSMA expression has emerged as a promising prognostic biomarker since its overexpression in radical prostatectomy specimens (RP) has been linked to disease recurrence. Aim of our study was to assess the prognostic value of PSMA on prostate biopsies (Bx) thus improving risk stratification at time of initial diagnosis. Methods: Immunohistochemistry for PSMA expression was performed on 294 Bx with corresponding RP, 621 primary tumor foci from 242 RP, 43 locally advanced or recurrent tumors, 34 lymph node metastases, 78 distant metastases, and 52 benign prostatic samples. Grade group, PSA, TNM-, and R-status were assessed as clinico-pathologic features. Primary endpoint was recurrence-free survival (RFS). Chi-square, ANOVA-analyses, Cox regression and log rank tests were performed for statistical analyses. Results: PSMA expression significantly associates with grade group and initial PSA level. Elevated PSMA expression on both RP and Bx significantly correlates with an increased risk of disease recurrence after curative surgery. 5-year RFS rates are 88.2%, 74.2%, 67.7%, and 26.8% for patients with no, low, medium, or high PSMA expression on Bx, respectively. Elevated PSMA level on Bx predict a 4-fold increased risk of disease recurrence independently from initial PSA and grade group on Bx. PSMA expression significantly increases during PCa progression. Conclusions: PSMA qualifies as an independent prognostic biomarker on Bx at time of initial diagnosis in addition to the established markers PSA and grade group. PSMA predicts disease recurrence following curative surgery and potentially improves the discrimination indolent vs. aggressive disease. We propose the routine assessment of PSMA expression on Bx for outcome prediction and risk stratification at time of initial diagnosis prior to treatment decision.

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Stopa, Brittany, Katherine Degen, Sharon Michelhaugh, Csaba Juhasz, and Sandeep Mittal. "TAMI-15. PROSTATE SPECIFIC MEMBRANE ANTIGEN EXPRESSION IN GLIOBLASTOMA TUMOR AND ENDOTHELIAL CELLS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi201. http://dx.doi.org/10.1093/neuonc/noab196.799.

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Abstract INTRODUCTION Prostate specific membrane antigen (PSMA) has emerged in recent years as a potential target for PET imaging of CNS tumors. Originally studied for imaging in prostate cancer, it was incidentally found to have selective uptake in some CNS tumors. Early studies have shown promise for PSMA tracer use in glioblastoma (GBM), but more research is needed to characterize the PSMA expression profile in GBM. METHODS Formalin-fixed paraffin-embedded tissues of 26 GBMs were immunostained with PSMA antibody. Stained sections were scored, using 5 images per tumor, in total 130 observations. Sections were assessed for extent and intensity of PSMA expression, in tumor cells and neovascular endothelial cells. Extent of expression: 0% (none), 1-9% (very low), 10-39% (low), 40-69% (moderate), > 70% (high). Intensity of expression: no staining (none); barely perceptible staining (low); readily apparent at low magnification (moderate); and maximum-intensity staining (high). RESULTS Extent of PSMA expression in tumor cells was mostly very low (76 out of 130, 58%), but intensity was often moderate (42, 32%), low (41, 32%), or high (39, 30%). The most prevalent combination was very low extent with low or moderate intensity (both 30, 23%). Endothelial cells were absent in 61 (47%) sections. Extent of expression in endothelial cells was mostly high (28, 41%), and intensity was often moderate (25, 36%) or high (20, 29%). The most prevalent combination was high extent with moderate (14, 20%) or high intensity (13, 19%). CONCLUSION PSMA expression was variable and was seen in both vascular endothelial cells and tumor cells. The mechanism of PSMA expression in GBM may not be straightforward, but rather may vary by cell type and tumor mutation status. Further tissue studies to understand the specific mechanism are needed to establish the potential use of PSMA PET as a neuroimaging modality in GBM.

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Banerjee, Sangeeta R., Baiqi Wang, Mrudula Pullambhatla, Catherine A. Foss, Martin G. Pomper, and Russell H. Morgan. "Albumin-based nanoformulation for prostate-specific membrane antigen (PSMA)." Nuclear Medicine and Biology 41, no. 7 (August 2014): 641–42. http://dx.doi.org/10.1016/j.nucmedbio.2014.05.135.

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Chang, Sam S., and Warren D. W. Heston. "The clinical role of prostate-specific membrane antigen (PSMA)." Urologic Oncology: Seminars and Original Investigations 7, no. 1 (January 2002): 7–12. http://dx.doi.org/10.1016/s1078-1439(01)00124-7.

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Vamadevan, Shankar, Deepa Shetty, Ken Le, Chuong Bui, Robert Mansberg, and Han Loh. "Prostate-Specific Membrane Antigen (PSMA) Avid Pancreatic Neuroendocrine Tumor." Clinical Nuclear Medicine 41, no. 10 (October 2016): 804–6. http://dx.doi.org/10.1097/rlu.0000000000001308.

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Peng, Wei, Lizheng Guo, Ruoyi Tang, Xiuju Liu, Rui Jin, Jin-Tang Dong, Chun-gen Xing, and Wei Zhou. "Sox7 negatively regulates prostate-specific membrane antigen (PSMA) expression through PSMA-enhancer." Prostate 79, no. 4 (November 28, 2018): 370–78. http://dx.doi.org/10.1002/pros.23743.

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Kessel, Katharina, Robert Seifert, Matthias Weckesser, Martin Boegemann, Sebastian Huss, Clemens Kratochwil, Uwe Haberkorn, Frederik Giesel, and Kambiz Rahbar. "Prostate-specific membrane antigen and fibroblast activation protein distribution in prostate cancer: preliminary data on immunohistochemistry and PET imaging." Annals of Nuclear Medicine 36, no. 3 (December 2, 2021): 293–301. http://dx.doi.org/10.1007/s12149-021-01702-8.

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Abstract Introduction Fibroblast activation protein (FAP) has been recently presented as new imaging target for malignant diseases and offers high contrast to surrounding normal tissue. FAP tracer uptake has been reported in various tumor entities. The aim of this study was to compare FAP and Prostate-specific membrane antigen (PSMA) expression in primary prostate cancer employing histological analyses and PET imaging in two small patient collectives. Methods Two independent small patient collectives were included in this study. For cohort A, data of 5 prostate cancer patients and 3 patients with benign prostate hyperplasia were included. Patients with prostate cancer were initially referred for PSMA PET staging. Radical prostatectomy was performed in all patients and prostate specimen of patients and biopsies of healthy controls were available for further evaluation. Histological workup included HE and immunohistochemistry using PSMA Ab, FAP Ab. Cohort B consists of 6 Patients with diagnosed mCRPC and available PSMA as well as FAP PET. Results Patients with proven prostate cancer infiltration exhibited strong positivity for PSMA in both primary tumors and lymph node metastases while stainings for FAP were found positive in some cases, but not all (2/5). Controls with BPH presented moderate PSMA staining and in one case also with a positive FAP staining (1/3). PET imaging with FAP seemed to result in more precise results in case of low PSMA expression than PSMA-PET. Conclusions While PSMA staining intensity is a valid indicator of prostate cancer in both primary tumor and lymph node metastases, the expression of FAP seems to be heterogeneous but not necessarily linked to cancer-associated fibroblasts. It is also present in inflammation-associated myofibroblasts. Therefore, its ultimate role in prostate cancer diagnosis remains a subject of discussion.

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DiPippo, Vincent A., Wells W. Magargal, Sameer M. Moorji, Jose D. Murga, and William C. Olson. "Antiandrogen modulation of prostate-specific membrane antigen (PSMA): Dynamics and synergy with PSMA-targeted therapy." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e16007-e16007. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e16007.

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e16007 Background: Recent approvals of four new prostate cancer (PCa) drugs and a growing number of pipeline agents have created opportunities for designing rational drug combinations. Potent antiandrogens such as enzalutamide and abiraterone affect expression of a host of androgen-regulated molecules, including those that represent targets for therapy. One such target is PSMA, a well-characterized cell-surface antigen abundant on prostate cancer cells. PSMA ADC is a PSMA-targeted antibody-drug conjugate currently in phase II clinical testing, comprised of a fully human IgG1 mAb conjugated to vcMMAE (valine-citrulline monomethylauristatin E). Here we examined the kinetics and reversibility of PSMA induction by potent antiandrogens and their associated effects on the preclinical activity of PSMA ADC. Methods: Androgen-dependent and -independent PCa cell lines with varying basal levels of PSMA expression were cultured for up to one month in the presence of enzalutamide or abiraterone, followed by drug washout. Cells were tested for PSMA expression over time and for susceptibility to cytotoxicity by PSMA ADC. Potential drug synergy or antagonism was evaluated using the combination index method. Results: Enzalutamide (1 mM) increased PSMA expression by approximately 2.5-fold in LNCaP (androgen-dependent) and C4-2 (androgen-independent) cells, with maximal expression observed after approximately 4 weeks’ culture. PSMA expression returned to basal levels within days following removal of enzalutamide from the culture. Enzalutamide and PSMA ADC exhibited synergistic antitumor activity in LNCaP and C4-2 cells (P < 0.05). Similar results were observed for abiraterone in C4-2 cells. Less induction of PSMA expression by antiandrogens and modest effects on cytotoxicity were observed using 22Rv1 cells, an androgen-independent cell line with low basal expression of PSMA. Conclusions: Enzalutamide and abiraterone significantly and reversibly augmented PSMA expression and potentiated the activity of PSMA ADC in PCa cell lines in vitro. The findings support clinical exploration of regimens that combine potent antiandrogens and PSMA-targeted therapies.

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Aras, Omer, Stefan Harmsen, Richard Ting, and Haluk B. Sayman. "225Actinium-labeled prostate-specific membrane antigen targeting peptide induces complete response in a metastatic prostate cancer patient." Acta Radiologica Open 10, no. 5 (May 2021): 205846012110225. http://dx.doi.org/10.1177/20584601211022509.

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Targeted radionuclide therapy has emerged as a promising and potentially curative strategy for high-grade prostate cancer. However, limited data are available on efficacy, quality of life, and pretherapeutic biomarkers. Here, we highlight the case of a patient with prostate-specific membrane antigen (PSMA)-positive metastatic castrate-resistant prostate cancer who displayed complete response to 225Ac-PSMA-617 after having been resistant to standard-of-care therapy, then initially partially responsive but later resistant to subsequent immunotherapy, and resistant to successive 177Lu-PSMA-617. In addition, the patient’s baseline germline mutation likely predisposed him to more aggressive disease.

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Han, Sangwon, Sungmin Woo, Yong-il Kim, Jae-Lyun Lee, Andreas G. Wibmer, Heiko Schoder, Jin-Sook Ryu, and Hebert Alberto Vargas. "Concordance between Response Assessment Using Prostate-Specific Membrane Antigen PET and Serum Prostate-Specific Antigen Levels after Systemic Treatment in Patients with Metastatic Castration Resistant Prostate Cancer: A Systematic Review and Meta-Analysis." Diagnostics 11, no. 4 (April 7, 2021): 663. http://dx.doi.org/10.3390/diagnostics11040663.

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Prostate-specific membrane antigen positron emission tomography (PSMA PET) has recently gained interest as a promising tool for treatment response evaluation in metastatic castration-resistant prostate cancer (CRPC). We performed a systematic review and meta-analysis assessing the concordance between response evaluation using PSMA PET and serum prostate-specific antigen (PSA) level after systemic treatment and the association between PSMA PET and overall survival in metastatic CRPC patients. PubMed, Embase, and Cochrane library databases were searched until August 2020. Studies that reported the concordance between PSMA PET and PSA response were included. PSMA PET and PSA response evaluation were dichotomized into response vs. non-response to construct two-by-two contingency tables; an ≥30% increase in PSMA PET according to PET Response Criteria in Solid Tumors 1.0 and as an increase in serum PSA level of ≥25% as per Prostate Cancer Working Group 3 guidelines were defined as non-response. The percent agreement rates were pooled using random-effect model. Ten studies (268 patients) were included. The concordance rates ranged 0.50–0.84 with a pooled proportion of 0.73 (95% confidence interval 0.67–0.79). Patients were treated with 177Lu-PSMA therapy in five, chemotherapy in three, 223Ra in one, and more than one type in one study. Various PET parameters were used: the most widely evaluated was PSMA tumor volume (PSMA-TV). Similar proportions were found across different therapeutic agents, PET response parameters, and regarding directionality of discordance (PSA response/PSMA non-response vs. PSMA response/PSA non-response). Two studies reported that a decrease in PSMA-TV was associated with better overall survival. PSMA PET and PSA response assessments were discordant in nearly a fourth of metastatic CRPC patients. Further studies are warranted to establish the clinical meaning of this discordance and define appropriate management for such clinical situation.

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von Eyben, Finn Edler, Glenn Bauman, Daniel S. Kapp, Irene Virgolini, and Giovanni Paganelli. "On the Way for Patients with Prostate Cancer to the Best Use of PSMA." International Journal of Molecular Sciences 23, no. 5 (February 24, 2022): 2478. http://dx.doi.org/10.3390/ijms23052478.

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48

Froehner, Michael, Marieta Toma, Klaus Zöphel, Vladimir Novotny, Michael Laniado, and Manfred P. Wirth. "PSMA-PET/CT-Positive Paget Disease in a Patient with Newly Diagnosed Prostate Cancer: Imaging and Bone Biopsy Findings." Case Reports in Urology 2017 (2017): 1–3. http://dx.doi.org/10.1155/2017/1654231.

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A 67-year-old man diagnosed with Gleason score4+5=9clinically localized prostate cancer with68Ga-labeled prostate-specific membrane antigen-targeted ligand positron emission tomography/computed tomography (PSMA-PET/CT) positive Paget bone disease is described. Immunohistochemical staining revealed weak PSMA positivity of the bone lesion supporting the hypothesis that neovasculature might explain positive PSMA-PET/CT findings in Paget disease.

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Hermann, Robert M., Manoutschehr Djannatian, Norbert Czech, and Mirko Nitsche. "Prostate-Specific Membrane Antigen PET/CT: False-Positive Results due to Sarcoidosis." Case Reports in Oncology 9, no. 2 (August 17, 2016): 457–63. http://dx.doi.org/10.1159/000447688.

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We report on a 72-year-old male patient who developed sarcoidosis of the mediastinal lymph nodes, the liver, and the prostate 11 years ago. Seven years later, he underwent transurethral resection of the prostate by laser due to hematuria. Pathology of the resected chips showed a ‘granulomatous prostatitis with epitheloid cells’. Malignancy was histologically excluded at that time. Four years later, he was diagnosed with an undifferentiated prostate carcinoma, with a Gleason score of 5 + 4 = 9. After initiation of antihormonal therapy, he underwent radical prostatectomy and pelvic lymphadenectomy, which revealed a pT3b pN1 carcinoma with infiltrated resection margins. Three months later, the prostate-specific antigen level was 1.4 ng/ml, and a local recurrence was suspected by ultrasound; consequently, a 68Ga-prostate-specific membrane antigen (PSMA) PET/CT was performed. This examination seemed to confirm the local recurrence, a right pelvic lymph node metastasis, and a hepatic metastasis. However, ultrasound with contrast medium could not confirm the metastatic spread to the liver. In palliative intention, radiotherapy of the pelvis was done. After 50 Gy, the supposed recurrence had markedly shrunk, and an additional boost dose with 16.2 Gy was applied. Two years later, the patient is still free of disease. Due to this clinical development, we doubt the diagnosis of a fulminant progression of the prostate cancer as suspected by PSMA-PET/CT. Instead, we suspect a recurrence of the previously proven sarcoidosis leading to false-positive results. Our focus in this report is on the interaction between PSMA-PET/CT and sarcoidosis. Another report on a case of sarcoidosis of the spleen seems to confirm this possibility [Kobe et al: Clin Nucl Med 2015;40: 897–898].

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Wang, Lei, Lei Tang, Yingjie Liu, Hao Wu, Ziang Liu, Jin Li, Yue Pan, and Engin U. Akkaya. "Prostate-specific membrane antigen (PSMA) targeted singlet oxygen delivery via endoperoxide tethered ligands." Chemical Communications 58, no. 12 (2022): 1902–5. http://dx.doi.org/10.1039/d1cc05810j.

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A PSMA targeting ligand is functionalized with endoperoxides which thermally release singlet oxygen. The results show that this modular design results in significantly more cell death in PSMA-expressing prostate cancer cells.

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