scholarly journals PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3967
Author(s):  
Mohamed El Fakiri ◽  
Nicolas M. Geis ◽  
Nawal Ayada ◽  
Matthias Eder ◽  
Ann-Christin Eder
Keyword(s):  
Prostate Cancer ◽  
Radionuclide Therapy ◽  
Targeted Radionuclide Therapy ◽  
Castration Resistant Prostate Cancer ◽  
International Visibility ◽  
Castration Resistant ◽  
Current State ◽  
Prostate Cancer Therapy ◽  
Recent Developments ◽  
Hormone Refractory

Prostate cancer (PC) is the second most common cancer among men, with 1.3 million yearly cases worldwide. Among those cancer-afflicted men, 30% will develop metastases and some will progress into metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis and median survival time that ranges from nine to 13 months. Nevertheless, the discovery of prostate specific membrane antigen (PSMA), a marker overexpressed in the majority of prostatic cancerous tissue, revolutionised PC care. Ever since, PSMA-targeted radionuclide therapy has gained remarkable international visibility in translational oncology. Furthermore, on first clinical application, it has shown significant influence on therapeutic management and patient care in metastatic and hormone-refractory prostate cancer, a disease that previously had remained immedicable. In this article, we provide a general overview of the main milestones in the development of ligands for PSMA-targeted radionuclide therapy, ranging from the firstly developed monoclonal antibodies to the current state-of-the-art low molecular weight entities conjugated with various radionuclides, as well as potential future efforts related to PSMA-targeted radionuclide therapy.

scholarly journals PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617

2016 ◽  
Vol 57 (8) ◽  
pp. 1170-1176 ◽  
Author(s):  
C. Kratochwil ◽  
F. L. Giesel ◽  
M. Stefanova ◽  
M. Bene ova ◽  
M. Bronzel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radionuclide Therapy ◽  
Targeted Radionuclide Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals PSMA targeting in metastatic castration-resistant prostate cancer: where are we and where are we going?

2021 ◽  
Vol 13 ◽  
pp. 175883592110538
Author(s):  
Anne-Laure Giraudet ◽  
David Kryza ◽  
Michael Hofman ◽  
Aurélie Moreau ◽  
Karim Fizazi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Membrane Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Treatment ◽  
Normal Tissues ◽  
Drug Conjugates ◽  
Castration Resistant ◽  
Current State ◽  
Important Addition ◽  
Specific Membrane

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.

scholarly journals Humanization, Radiolabeling and Biodistribution Studies of an IgG1-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications

2021 ◽  
Vol 14 (12) ◽  
pp. 1251
Author(s):  
Joanna Strand ◽  
Kjell Sjöström ◽  
Urpo J. Lamminmaki ◽  
Oskar Vilhelmsson Timmermand ◽  
Sven-Erik Strand ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Binding ◽  
Hek293 Cells ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biodistribution Studies ◽  
Indium 111 ◽  
Hormone Refractory ◽  
Theranostic Applications

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications.

Chemotherapy in hormone-refractory prostate cancer: Docetaxel with and without VT122.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16062-e16062
Author(s):  
Gouri Shankar Bhattacharyya ◽  
Newell Bascomb ◽  
Hemant Malhotra ◽  
Ghanashyam Biswas ◽  
Shailesh Arjun Bondarde
Keyword(s):  
Prostate Cancer ◽  
Randomized Study ◽  
Castration Resistant Prostate Cancer ◽  
Protein Levels ◽  
Reactive Protein ◽  
End Point ◽  
Castration Resistant ◽  
Number Of Patients ◽  
Duration Of Response ◽  
Hormone Refractory

e16062 Background: Randomized study in metastatic castration resistant prostate cancer treated with docetaxel and the benefit of adding VT122. Methods: Castration resistant prostate cancer with bone metastasis, symptomatic were treated with docetaxel 75 mg/m2 every 3 week and prednisolone with continued androgen suppression, LHRH analogue and zoledronic acid, every 28 days with or without VT122. VT122 is a drug combination of etodolac, a COX-2 inhibitor and propranolol, a beta blocker with anti angiogenic properties; this combination has previously been shown to be anti cachectic, anti neoplastic.The dose of etodolac was titrated by C-reactive protein levels to a maximum of 800 mg/day. The dose of propranolol was titrated to keep heart rate at around 60 b/min to 70 b/min. GCSF was allowed, all patients were given Calcium and VitaminD. The primary end point was time to progression, a composite end point of objective progression by RECIST criteria, PSA progression or pain progression, whichever occurred first was applied.The McGill questionnaire was applied to patients. Number of patients 69; 34 in docetaxel arm; 35 in VT122 arm. Age between 50-65 years. Taken from 3 centers with PS ECOG <2 controlled comorbidity with stable analgesic regime. All patients were planned for 6 cycles of docetaxel. Follow-up was for a period of two years. Results: Median age of 62 years with ECOG status 1 was seen in 88%. The median PSA value was seen as 138 ng/ml (10 - 600). 66% in both arms had measurable disease. Conclusions: Addition of VT122 improves response rates, duration of response and symptom scales along with 1-year survival which are statistically significant; toxicities are also significantly decreased and indicating increased efficacy and safety profile of docetaxel. The efficacy and control of toxicity and easy to administer makes this an attractive combination. [Table: see text]

scholarly journals 213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer

2017 ◽  
Vol 44 (6) ◽  
pp. 1099-1100 ◽  
Author(s):  
Mike Sathekge ◽  
Otto Knoesen ◽  
Marian Meckel ◽  
Moshe Modiselle ◽  
Mariza Vorster ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radionuclide Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

TACC2 Is an Androgen-Responsive Cell Cycle Regulator Promoting Androgen-Mediated and Castration-Resistant Growth of Prostate Cancer

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Survival Rates ◽  
Tumor Formation ◽  
Castration Resistant Prostate Cancer ◽  
Cellular Models ◽  
Castration Resistant ◽  
Hormone Refractory ◽  
Immunocompromised Mice

Despite the existence of effective antiandrogen therapy for prostate cancer, the disease oftenprogresses to castration-resistant states. Elucidation of the molecular mechanisms underlying theresistance for androgen deprivation in terms of the androgen receptor (AR)-regulated pathwaysis a requisite to manage castration-resistant prostate cancer (CRPC). Using a ChIP-cloning strategy,we identified functional AR binding sites (ARBS) in the genome of prostate cancer cells. Wediscovered that a centrosome- and microtubule-interacting gene, transforming acidic coiled-coilprotein 2 (TACC2), is a novel androgen-regulated gene.Weidentified a functional AR-binding site(ARBS) including two canonical androgen response elements in the vicinity of TACC2 gene, inwhich activated hallmarks of histone modification were observed. Androgen-dependent TACC2induction is regulated by AR, as confirmed by AR knockdown or its pharmacological inhibitorbicalutamide. Using long-term androgen-deprived cells as cellular models of CRPC, we demonstratedthat TACC2 is highly expressed and contributes to hormone-refractory proliferation, assmall interfering RNA-mediated knockdown of TACC2 reduced cell growth and cell cycle progression.By contrast, in TACC2-overexpressing cells, an acceleration of the cell cycle was observed. Invivo tumor formation study of prostate cancer in castrated immunocompromised mice revealedthat TACC2 is a tumor-promoting factor. Notably, the clinical significance of TACC2 was demonstratedby a correlation between high TACC2 expression and poor survival rates. Taken togetherwith the critical roles of TACC2 in the cell cycle and the biology of prostate cancer, we infer thatthe molecule is a potential therapeutic target in CRPC

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