scholarly journals A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Srikanth Boinapally ◽  
Hye-Hyun Ahn ◽  
Bei Cheng ◽  
Mary Brummet ◽  
Hwanhee Nam ◽  
...  
Keyword(s):  
Specific Antigen ◽  
Prostate Specific Membrane Antigen ◽  
Toxicity Profile ◽  
Microtubule Inhibitor ◽  
Promising Target ◽  
Significant Survival ◽  
Targeting Ability ◽  
Immunocompetent Mice ◽  
Specific Membrane

AbstractProstate-specific membrane antigen (PSMA) is a promising target for the treatment of advanced prostate cancer (PC) and various solid tumors. Although PSMA-targeted radiopharmaceutical therapy (RPT) has enabled significant imaging and prostate-specific antigen (PSA) responses, accumulating clinical data are beginning to reveal certain limitations, including a subgroup of non-responders, relapse, radiation-induced toxicity, and the need for specialized facilities for its administration. To date non-radioactive attempts to leverage PSMA to treat PC with antibodies, nanomedicines or cell-based therapies have met with modest success. We developed a non-radioactive prodrug, SBPD-1, composed of a small-molecule PSMA-targeting moiety, a cancer-selective cleavable linker, and the microtubule inhibitor monomethyl auristatin E (MMAE). SBPD-1 demonstrated high binding affinity to PSMA (Ki = 8.84 nM) and selective cytotoxicity to PSMA-expressing PC cell lines (IC50 = 3.90 nM). SBPD-1 demonstrated a significant survival benefit in two murine models of human PC relative to controls. The highest dose tested did not induce toxicity in immunocompetent mice. The high specific targeting ability of SBPD-1 to PSMA-expressing tumors and its favorable toxicity profile warrant its further development.

A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile

2020 ◽  
Author(s):  
Srikanth Boinapally ◽  
Hye-Hyun Ahn ◽  
Bei Cheng ◽  
Mary Brummet ◽  
Hwanhee Nam ◽  
...  
Keyword(s):  
Specific Antigen ◽  
Prostate Specific Membrane Antigen ◽  
Toxicity Profile ◽  
Microtubule Inhibitor ◽  
Promising Target ◽  
Significant Survival ◽  
Targeting Ability ◽  
Immunocompetent Mice ◽  
Specific Membrane

Abstract Prostate-specific membrane antigen (PSMA) is a promising target for the treatment of advanced prostate cancer (PC) and various solid tumors. Although PSMA-targeted radiopharmaceutical therapy (RPT) has enabled significant imaging and prostate-specific antigen (PSA) responses, accumulating clinical data are beginning to reveal certain limitations, including a subgroup of non-responders, relapse, radiation-induced toxicity, and the need for specialized facilities for its administration. To date non-radioactive attempts to leverage PSMA to treat PC with antibodies, nanomedicines or cell-based therapies have met with modest success. We developed a non-radioactive prodrug, SBPD-1, composed of a small-molecule PSMA-targeting moiety, a cancer-selective cleavable linker, and the microtubule inhibitor monomethyl auristatin E (MMAE). SBPD-1 demonstrated high binding affinity to PSMA (Ki = 8.84 nM) and selective cytotoxicity to PSMA-expressing PC cell lines (IC50 = 3.90 nM). SBPD-1 demonstrated a significant survival benefit in two murine models of human PC relative to controls. The highest dose tested did not induce toxicity in immunocompetent mice. The high specific targeting ability of SBPD-1 to PSMA-expressing tumors and its favorable toxicity profile warrant its further development.

Can 68Ga-PSMA PET/CT-derived prostate-specific membrane antigen expression parameters predict prostate-specific antigen response to enzalutamide treatment?

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Savaş Karyağar ◽  
Osman Güven ◽  
Sevda Sağlampinar Karyağar ◽  
Serdar Arici ◽  
Oğuzhan Selvi ◽  
...  
Keyword(s):  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Antigen Expression ◽  
Prostate Specific Membrane Antigen ◽  
Psma Pet ◽  
Pet Ct ◽  
Specific Membrane

THE FIRST EXPERIENCE OF PERFORMING COMBINED POSITRONEMISSION WITH COMPUTED TOMOGRAPHY WITH PROSTATE-SPECIFIC MEMBRANE ANTIGEN LABELED WITH GALLIUM-68 IN PATIENTS WITH MINIMAL LEVEL OF PROSTATE-SPECIFIC ANTIGEN AFTER RADICAL PROSTATECTOMY

2018 ◽  
Vol 64 (4) ◽  
pp. 508-514
Author(s):  
Mariya Ignatova ◽  
Marina Tlostanova ◽  
Andrey Stanzhevskiy
Keyword(s):  
Computed Tomography ◽  
Radical Prostatectomy ◽  
Structural Changes ◽  
Visual Analysis ◽  
Specific Antigen ◽  
Prostate Specific Membrane Antigen ◽  
Radiographic Findings ◽  
Pet Ct ◽  
Gallium 68 ◽  
Specific Membrane

To assess diagnostic capabilities of new receptor-specific radiopharmaceutical - prostate-specific membrane antigen labeled with gallium-68 (68Ga-PSMA) 66 patients with prostate cancer (PC) after radical prostatectomy underwent combined positron emission with computed tomography (PET/CT). In 61/66 cases PSA level was 0,2-1,0 ng/ml, in 5/66 it did not exceed 0,2 ng/ml. The processing of the results concluded in a visual analysis of the images. In 45/66 patients with PET foci of hyperfaxation of radiopharmaceutical were detected. At the same time structural changes in CT were determined only in 34/45 patients. PSMA-positive cases, not accompanied by radiographic findings, were attributed to false positive results. Indicators of PET/CT information without taking into account X-ray parameters of PSMA-positive changes had a greater diagnostic significance of the method in this category of patients. PET/CT with 68Ga-PSMA is a promising method for diagnosing biochemical recurrence of PC at low PSA values.

Heterogeneity of prostate-specific membrane antigen (PSMA) expression in classic and apoptotic circulating tumor cells (CTC) in metastatic castration-resistant prostate cancer (mCRPC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 198-198 ◽  
Author(s):  
Karen A. Autio ◽  
Aseem Anand ◽  
Rachel Krupa ◽  
Jessica Louw ◽  
Zaina Arslan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Specific Antigen ◽  
Cytotoxic Agents ◽  
Prostate Specific Membrane Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Membrane ◽  
Psma Expression

198 Background: Prostate-specific membrane antigen (PSMA) is a folate hydrolase expressed on the surface of PC cells that has been used as a target to detect disease and selectively deliver cytotoxic agents and radionuclides. The ability to detect PSMA levels on circulating tumor cells (CTCs) may identify patients likely to benefit from such targeted therapy. Technology developed by Epic Sciences utilizes high definition imaging of plated nucleated cells. Methods: Blood samples were obtained from patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Cells were stained for CK, CD45, PSMA and categorized as classic CTC (CK+, CD45-, intact/morphologically distinct nuclei) or apoptotic CTC (CK+, CD45-, morphology suggesting apoptosis). Clinical data including treatment, metastatic sites, Veridex CellSearch CTC enumeration, prostate-specific antigen, and alkaline phosphatase was collected. Results: Fourteen pts with mCRPC, including eight with serial samples were analyzed (33 samples in total). At the first draw (t1), classic CTC were detected in 13 pts (93%), (median two cells/ml, range 0 to 40 cells/ml) and apoptotic CTC in 14 pts (100%) (median four cells/ml, range 1 to 18 cells/ml), including six pts (42%) with no CTC by Veridex CellSearch. PSMA expression was detected in five pts (36%) with classic CTC of which a median of 32% of cells (range 5 to 100%) expressed the antigen. Similar intra-patient heterogeneity was seen for the 10 pts (71.4%) with PSMA+ apoptotic CTCs (median 33.5%, range 11 to 75% cells). During treatment, often with more complete androgen suppression, PSMA was detected in 3 of the 8 (38%) pts with no PSMA+ classic CTCs at t1. The presence of PSMA expression in apoptotic CTCs did not appear to change while on therapy. Conclusions: A larger percentage of PSMA expression was seen in mCRPC pts in apoptotic CTC (10 out of 14) than classic CTC (5 out of 14) at t1, with intra-patient cell heterogeneity of PSMA expression in both CTC populations. Serial measures suggest dynamic changes in PSMA expression over time. The threshold of detectable cells and proportion and degree of PSMA expression that associates with drug sensitivity is unknown. Larger samples of pts at discrete time points on therapy are underway to further elucidate the potential clinical relevance.

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