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TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice

TBR-760 (formerly BIM-23A760) is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R) and SST type 2 (SSTR2) receptors. Studies have shown that chimeric DA-SST compounds are more efficacious than individual DA and/or SST analogues, either alone or...

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Autores principales: Halem, Heather A, Hochgeschwender, Ute, Rih, Jeong Keun, Nelson, Richard, Johnson, G Allan, Thiagalingam, Arunthi, Culler, Michael D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375803/
https://www.ncbi.nlm.nih.gov/pubmed/32591776
http://dx.doi.org/10.1210/endocr/bqaa101
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author Halem, Heather A
Hochgeschwender, Ute
Rih, Jeong Keun
Nelson, Richard
Johnson, G Allan
Thiagalingam, Arunthi
Culler, Michael D
author_facet Halem, Heather A
Hochgeschwender, Ute
Rih, Jeong Keun
Nelson, Richard
Johnson, G Allan
Thiagalingam, Arunthi
Culler, Michael D
author_sort Halem, Heather A
collection PubMed
description TBR-760 (formerly BIM-23A760) is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R) and SST type 2 (SSTR2) receptors. Studies have shown that chimeric DA-SST compounds are more efficacious than individual DA and/or SST analogues, either alone or combined, in inhibiting secretion from primary cultures of human somatotroph and lactotroph tumor cells. Nonfunctioning pituitary adenomas (NFPAs) express both D2R and SSTR2 and, consequently, may respond to TBR-760. We used a mouse model with the pro-opiomelanocortin (POMC) gene knocked out that spontaneously develops aggressive NFPAs. Genomic microarray and DA and SST receptor messenger RNA expression analysis indicate that POMC KO mouse tumors and human NFPAs have similar expression profiles, despite arising from different cell lineages, establishing POMC KO mice as a model for study of NFPAs. Treatment with TBR-760 for 8 weeks resulted in nearly complete inhibition of established tumor growth, whereas tumors from vehicle-treated mice increased in size by 890 ± 0.7%. Comparing TBR-760 with its individual DA and SST components, TBR-760 arrested tumor growth. Treatment with equimolar or 10×-higher doses of the individual SST or DA agonists, either alone or in combination, had no significant effect. One exception was the lower dose of DA agonist that induced modest suppression of tumor growth. Only the chimeric compound TBR-760 arrested tumor growth in this mouse model of NFPA. Further, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a therapy for patients with NFPA.
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spelling pubmed-73758032020-07-27 TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice Halem, Heather A Hochgeschwender, Ute Rih, Jeong Keun Nelson, Richard Johnson, G Allan Thiagalingam, Arunthi Culler, Michael D Endocrinology Research Articles TBR-760 (formerly BIM-23A760) is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R) and SST type 2 (SSTR2) receptors. Studies have shown that chimeric DA-SST compounds are more efficacious than individual DA and/or SST analogues, either alone or combined, in inhibiting secretion from primary cultures of human somatotroph and lactotroph tumor cells. Nonfunctioning pituitary adenomas (NFPAs) express both D2R and SSTR2 and, consequently, may respond to TBR-760. We used a mouse model with the pro-opiomelanocortin (POMC) gene knocked out that spontaneously develops aggressive NFPAs. Genomic microarray and DA and SST receptor messenger RNA expression analysis indicate that POMC KO mouse tumors and human NFPAs have similar expression profiles, despite arising from different cell lineages, establishing POMC KO mice as a model for study of NFPAs. Treatment with TBR-760 for 8 weeks resulted in nearly complete inhibition of established tumor growth, whereas tumors from vehicle-treated mice increased in size by 890 ± 0.7%. Comparing TBR-760 with its individual DA and SST components, TBR-760 arrested tumor growth. Treatment with equimolar or 10×-higher doses of the individual SST or DA agonists, either alone or in combination, had no significant effect. One exception was the lower dose of DA agonist that induced modest suppression of tumor growth. Only the chimeric compound TBR-760 arrested tumor growth in this mouse model of NFPA. Further, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a therapy for patients with NFPA. Oxford University Press 2020-06-27 /pmc/articles/PMC7375803/ /pubmed/32591776 http://dx.doi.org/10.1210/endocr/bqaa101 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Halem, Heather A
Hochgeschwender, Ute
Rih, Jeong Keun
Nelson, Richard
Johnson, G Allan
Thiagalingam, Arunthi
Culler, Michael D
TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice
title TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice
title_full TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice
title_fullStr TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice
title_full_unstemmed TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice
title_short TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice
title_sort tbr-760, a dopamine-somatostatin compound, arrests growth of aggressive nonfunctioning pituitary adenomas in mice
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375803/
https://www.ncbi.nlm.nih.gov/pubmed/32591776
http://dx.doi.org/10.1210/endocr/bqaa101
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