TBR-760, a Dopamine-Somatostatin Compound, Arrests Tumor Growth of Aggressive Non-Functioning Pituitary Adenomas in Mice
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ABSTRACT:
PROVIDER: PRJNA637505 | ENA |
REPOSITORIES: ENA
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Project 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. Non-functioning pituitary adenomas (NFPAs) express both D2R and SSTR2 and, consequently, may respond to TBR-760. We utilized a mouse model with the pro-opiomelanocortin (POMC) gene knocked-out that spontaneously develops aggressive NFPAs. Both genomic microarray and DA and SST receptor mRNA expression analysis indicate that POMC KO mouse tumors and human NFPAs have similar expression profiles, establishing POMC KO mice as a valid 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%. These results support the development of TBR-760 as a therapy for patients with NFPA.
2020-06-06 | GSE151857 | GEO
Project 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.
| S-EPMC7375803 | biostudies-literature
Project description:Transcriptional changes associated with functioning and non-functioning Pituitary adenomas.
| PRJNA831798 | ENA
Project description:Non-functioning pituitary adenomas AmpliSeq data
| PRJNA563652 | ENA
Project description:This dataset contains high throughput sequencing data from Non-functioning pituitary adenomas (NFPAs) together with associated control sections of healthy pituitary which was obtained from formalin-fixed paraffin embeded samples. All of the samles come from patients of Maria Sklodowska-Curie Memorial Cancer Center in Warsaw. All the samples were sequenced using Ion Torrent technology in Maria Sklodwoska-Curie Memorial Cancer Center in Warsaw. They were further processed and used to perform complex analyses using other high-throughput data.
2019-09-04 | GSE136781 | GEO
Project description:Methylobacterium organophilum DSM 760 genome sequencing
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Project description:Dysregulation of microRNAs (miRNAs) plays a critical role in the development of intervertebral disc degeneration (IDD). In this study, we present evidence from in vitro and in vivo research to elucidate the mechanism underlying the role of miR-760 in IDD. miRNA microarray and quantitative reverse transcription-polymerase chain reaction were used to determine the miRNA profiles in patients with IDD. Functional analysis was performed to evaluate the role of miR-760 in the pathogenesis of IDD. Luciferase reporter and western blotting assays were used to confirm the miRNA targets. The expression of miR-760 was significantly decreased in degenerative nucleus pulposus (NP) cells and negatively correlated with disc degeneration grade. Functional assays demonstrated that miR-760 delivery significantly increased NP cell proliferation and promoted the expression of collagen II and aggrecan. Moreover, MyD88 was identified as a target gene of miR-760. miR-760 effectively suppressed MyD88 expression by interacting with the 3′-untranslated region, which was abolished by miR-760 binding site mutations. An in vivo experiment using an IDD mouse model showed that the upregulation of miR-760 could effectively suspend IDD. Therefore, miR-760 was found to play an important role in IDD and can be used as a promising therapeutic target for the treatment of patients with IDD.
2022-03-17 | E-MTAB-11554 | biostudies-arrayexpress
Project description:Total RNA-sequencing of FACs isolated nucleus accumbens somatostatin interneuron nuclei Somatostatin interneuron loss in multiple cortical brain regions has been observed postmortem in humans with several neuropsychiatric disorders and their loss is proposed to underlie some common pathological changes in circuit function across numerous syndromes. However, somatostatin interneurons in the nucleus accumbens (NAc), a key brain reward region, remain poorly understood due to the fact that these cells account for <1% of NAc neurons. Here, we used Flouresence activated cell sorting to isolate nuclei of somatostatin-expressing interneurons in the Nucleus Accumbens from individual SST-TLG498 reporter mice that express membrane bound EGFP-F specifically in somatostatin-expressing neurons. We then performed cell-type specific Total RNA-sequencing to characterize the entire transcriptome of NAc somatostatin interneurons after repeated exposure (7 days) to either saline or cocaine. We identified a wide variety of coding and non-coding transcripts that were expressed at high levels and were differentially expressed between saline and cocaine treated mice. Repeated cocaine administration induces transcriptome-wide changes in gene expression within NAc somatostatin interneurons, with particular regulation of transcripts related to neural plasticity. Our results identify alterations in NAc induced by cocaine in a sparse population of somatostatin interneurons, and illustrate the value of studying brain diseases using cell type-specific whole transcriptome RNA-sequencing to identify novel neurpathophysiology.
2018-07-03 | GSE116484 | GEO
Project description:Assemblies of 760 MetaHIT metagenomes used in a pangenomic study
| PRJEB28245 | ENA