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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE151857 | GEO | 2020/06/06

REPOSITORIES: GEO

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Project description:Purpose: Neuropeptide signaling has been reported to impact neurogenesis in the central nervous system. However, these studies have typically been conducted using pharmacological agents in ex vivo preparations, and in vivo evidence for their developmental function is generally lacking. The goal of this study is to identify the impact of somatostatin signaling on retinal neurogenesis and development both ex vivo and in vivo. Methods: Mouse retinal explants grown ex vivo from E14-P0 and treated with a range of doses of agonist for the somatostatin receptor Sstr2 were multiplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Retinas from P0 littermates representing an allelic series (+/+, +/-, -/-) of Sstr2 KO mice were mutliplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Retinas from P14 littermates representing an allelic series (+/+, +/-, -/-) of Sstr2 KO mice were mutliplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Sequencing was performed on an illumina sequencer. Bcl files were analyzed by Cellranger. Samples were deconvoluted with the deMULTIplex r package and clustering and gene expression analysis were performed with the Seurat and Monocle2 r packages. Results: Cell type proportions were found to be impacted by Sstr2 signaling ex vivo with increasing levels of Sstr2 agonist found to decrease photoreceptor proportion and increase primary progenitor proportion. Sstr2 KO was not found to have an impact on cell type proportion in vivo at either P0 or P14. Sstr2 pharmacologic manipulation and Sstr2 KO did produce complementary gene expression changes in neurogenic progenitors indicating that somatostatin signaling downregulates neurogenesis. Conclusions: Our study demonstrates a role for somatostatin in retinal development by downregulating neurogenesis in neurogenic progenitors. However, it also demonstrates that somatostatin signaling is dispensable for in vivo retinal development and likely redundant with other cell extrinsic signals released during the same period.

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

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