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

Endocrinology ◽  
2020 ◽  
Vol 161 (8) ◽  
Author(s):  
Heather A Halem ◽  
Ute Hochgeschwender ◽  
Jeong Keun Rih ◽  
Richard Nelson ◽  
G Allan Johnson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Pituitary Adenomas ◽  
Messenger Rna ◽  
Expression Profiles ◽  
Primary Cultures ◽  
Nonfunctioning Pituitary Adenomas ◽  
Mouse Tumors ◽  
The Individual

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. 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.

scholarly journals OR06-02 TBR-760, a Chimeric Somatostatin-Dopamine Compound, Arrests Aggressive Non-Functioning Pituitary Adenoma Growth In Vivo

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Heather A Halem ◽  
Ute Hochgeschwender ◽  
Arunthi Thiagalingam ◽  
Michael D Culler
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Pituitary Adenomas ◽  
Initial Study ◽  
Mouse Tumors ◽  
Inhibition Of Tumor Growth ◽  
Null Mutant Mice ◽  
The Individual

Abstract TBR-760 is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R; EC50 0.064nM) and SST type 2 (SSTR2; EC50 1.2nM) receptors. Prior studies have demonstrated that the chimeric DA-SST compounds are more potent and effective than either individual or combinations of individual DA and/or SST analogs in inhibiting secretion from pituitary adenomas. Non-functioning pituitary adenomas (NFPA) express high levels of D2R as well as lower levels of SSTRs, including the type 2 receptor (1), and thus have an appropriate receptor profile to respond to TBR-760. The present study examines the ability of TBR-760 to inhibit tumor growth in a mouse model of aggressive NFPA. Heterozygous and null mutant mice lacking one or both copies, respectively, of the pro-opiomelanocortin (POMC) gene (POMC-KO mice)(2) spontaneously develop aggressive, non-secreting pituitary adenomas (3). The POMC-KO mouse tumors have been shown to express D2R and SSTR2 at a similar level as human NFPAs (4). In addition, merging of microarray data (Affymetrix, U133 plus_2.0 and Mouse Genome 430 2.0 arrays), reveals 154 common gene signatures between human NFPAs and the POMC-KO mouse tumors. In an initial study, heterozygous POMC-KO mice with an established pituitary tumor of approx. 10mm3 (mean volume 8.9±0.3), as determined by MRI, were treated with a range of TBR-760 doses (0.125 to 12.5mg/kg, sc, QD) for 60 days. During that time, tumors in vehicle-treated mice increased in size by 890±0.7%, whereas all doses of TBR-760 tested resulted in a nearly complete inhibition of tumor growth from treatment initiation. We then compared the effect of the TBR-760 chimera with that of its individual SST agonist (SSTA) and DA agonist (DAA) components on tumor growth in the POMC-KO mice. As in the earlier study, TBR-760 treatment (1mg/kg, sc, QD), initiated when the mice had an established tumor of approx. 10mm3, completely arrested tumor growth during the 8 weeks of treatment (final mean tumor volume of 8.5±1.3mm3 vs. 54.61±10.6mm3 in vehicle-treated mice). Treatment with equimolar or 10x-higher doses of the individual SSTA or DAA, either alone or in combination, had no significant effect on tumor growth, except in the lower dose DAA group where a modest suppression of tumor growth was observed. These data demonstrate that only the dual DA-SST chimeric compound, TBR-760, completely arrested tumor growth in the POMC-KO mouse model of NFPA. Further, despite the highly aggressive nature of the POMC-KO tumors, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a medical therapy to prevent or arrest the growth of NFPAs and, potentially, to induce NFPA shrinkage. References: (1) Florio et al., 2008 Endocr Relat Cancer; 15: 583-596. (2) Yaswen et al., 1999 Nat Med; 9:1066-70 (3) Karpac J et al., 2006 Cell Mol Biol; 52: 47-52.

scholarly journals Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

2019 ◽  
Vol 110 (1-2) ◽  
pp. 119-129 ◽  
Author(s):  
Antonella Sesta ◽  
Maria Francesca Cassarino ◽  
Mariarosa Terreni ◽  
Alberto G. Ambrogio ◽  
Laura Libera ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Pituitary Adenomas ◽  
Expression Profiles ◽  
Primary Cultures ◽  
Acth Secretion ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease ◽  
Acth Secreting

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

scholarly journals circOMA1-Mediated miR-145-5p Suppresses Tumor Growth of Nonfunctioning Pituitary Adenomas by Targeting TPT1

2019 ◽  
Vol 104 (6) ◽  
pp. 2419-2434 ◽  
Author(s):  
Qiu Du ◽  
Bin Hu ◽  
Yajuan Feng ◽  
Zongming Wang ◽  
Xin Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pituitary Adenomas ◽  
Nonfunctioning Pituitary Adenomas

Radiosurgery for Nonfunctioning Pituitary Adenomas

Neurosurgery ◽  
2005 ◽  
Vol 56 (4) ◽  
pp. 699-705 ◽  
Author(s):  
Yoshiyasu Iwai ◽  
Kazuhiro Yamanaka ◽  
Katsunobu Yoshioka
Keyword(s):  
Tumor Growth ◽  
Pituitary Adenomas ◽  
Gamma Knife Radiosurgery ◽  
Growth Control ◽  
Cyst Formation ◽  
Morbidity Rate ◽  
Nonfunctioning Pituitary Adenomas ◽  
Long Term Follow Up

Abstract OBJECTIVE: We evaluated the effectiveness of gamma knife radiosurgery in the treatment of nonfunctioning pituitary adenomas. METHODS: Between January 1994 and December 1999, we treated 34 patients with nonfunctioning pituitary adenomas. Thirty-one of these patients were followed for more than 30 months. Their mean age was 52.9 years. All patients underwent resection before radiosurgery. In four patients, treatment was performed with staged radiosurgery. The treatment volume was 0.7 to 36.2 cm3 (median, 2.5 cm3). The treatment dose ranged from 8 to 20 Gy (median, 14.0 Gy) to the tumor margin. In 15 patients (48.4%), the tumor either compressed or was attached to the optic apparatus. The maximum dose to the optic apparatus was from 2 to 11 Gy (median, 8 Gy). RESULTS: Patients were followed for 30 to 108 months (median, 59.8 mo). The tumor size decreased in 18 patients (58.1%), remained unchanged in 9 patients (29.0%), and increased in four patients (12.9%). The 5-year actual tumor growth control rate was 93%. Among patients with tumor growth, two cases were secondary to cyst formation. Two patients (6.5%) required adrenal and thyroid hormonal replacement during the follow-up period after radiosurgery because of radiation-induced endocrinopathy. None of the patients sustained new cranial nerve deficits, which included optic neuropathy. CONCLUSION: In this series, radiosurgery had a high tumor growth control rate during the long-term follow-up period. Furthermore, we observed a low morbidity rate, with endocrinopathies and optic neuropathies. This low rate included even patients in whom the tumor compressed or was attached to the optic apparatus. We emphasize the necessity of long-term follow-up to evaluate late complications.

scholarly journals Enhanced LH action in transgenic female mice expressing hCGβ-subunit induces pituitary prolactinomas; the role of high progesterone levels

2010 ◽  
Vol 17 (3) ◽  
pp. 611-621 ◽  
Author(s):  
Petteri Ahtiainen ◽  
Victoria Sharp ◽  
Susana B Rulli ◽  
Adolfo Rivero-Müller ◽  
Veronika Mamaeva ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pituitary Adenomas ◽  
Cultured Cells ◽  
Gh3 Cells ◽  
Pituitary Cells ◽  
Promoting Effect ◽  
Female Mice ◽  
Mouse Tumors ◽  
Primary Mouse

The etiology of pituitary adenomas remains largely unknown, with the exception of involvement of estrogens in the formation of prolactinomas. We have examined the molecular pathogenesis of prolactin-producing pituitary adenomas in transgenic female mice expressing the human choriongonadotropin (hCG) β-subunit. The LH/CG bioactivity is elevated in the mice, with consequent highly stimulated ovarian progesterone (P4) production, in the face of normal estrogen secretion. Curiously, despite normal estrogen levels, large prolactinomas developed in these mice, and we provide here several lines of evidence that the elevated P4 levels are involved in the growth of these estrogen-dependent tumors. The antiprogestin mifepristone inhibited tumor growth, and combined postgonadectomy estradiol/P4 treatment was more effective than estrogen alone in inducing tumor growth. Evidence for direct growth-promoting effect of P4 was obtained from cultures of primary mouse pituitary cells and rat somatomammotroph GH3 cells. The mouse tumors and cultured cells revealed stimulation of the cyclin D1/cyclin-dependent kinase 4/retinoblastoma protein/transcription factor E2F1 pathway in the growth response to P4. If extrapolated to humans, and given the importance of endogenous P4 and synthetic progestins in female reproductive functions and their pharmacotherapy, it is relevant to revisit the potential role of these hormones in the origin and growth of prolactinomas.

scholarly journals Somatotropinomas, But Not Nonfunctioning Pituitary Adenomas, Maintain a Functional Apoptotic RET/Pit1/ARF/p53 Pathway That Is Blocked by Excess GDNF

Endocrinology ◽  
2014 ◽  
Vol 155 (11) ◽  
pp. 4329-4340 ◽  
Author(s):  
Esther Diaz-Rodriguez ◽  
Angela R. Garcia-Rendueles ◽  
Alejandro Ibáñez-Costa ◽  
Ester Gutierrez-Pascual ◽  
Montserrat Garcia-Lavandeira ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Primary Cultures ◽  
Survival Function ◽  
Pituitary Hormones ◽  
Rt Pcr ◽  
Steroidogenic Factor 1 ◽  
Apoptosis Pathway ◽  
Nonfunctioning Pituitary Adenomas ◽  
Enhancer Binding Protein ◽  
In Silico Studies

Abstract Acromegaly is caused by somatotroph cell adenomas (somatotropinomas [ACROs]), which secrete GH. Human and rodent somatotroph cells express the RET receptor. In rodents, when normal somatotrophs are deprived of the RET ligand, GDNF (Glial Cell Derived Neurotrophic Factor), RET is processed intracellularly to induce overexpression of Pit1 [Transcription factor (gene : POUF1) essential for transcription of Pituitary hormones GH, PRL and TSHb], which in turn leads to p19Arf/p53-dependent apoptosis. Our purpose was to ascertain whether human ACROs maintain the RET/Pit1/p14ARF/p53/apoptosis pathway, relative to nonfunctioning pituitary adenomas (NFPAs). Apoptosis in the absence and presence of GDNF was studied in primary cultures of 8 ACROs and 3 NFPAs. Parallel protein extracts were analyzed for expression of RET, Pit1, p19Arf, p53, and phospho-Akt. When GDNF deprived, ACRO cells, but not NFPAs, presented marked level of apoptosis that was prevented in the presence of GDNF. Apoptosis was accompanied by RET processing, Pit1 accumulation, and p14ARF and p53 induction. GDNF prevented all these effects via activation of phospho-AKT. Overexpression of human Pit1 (hPit1) directly induced p19Arf/p53 and apoptosis in a pituitary cell line. Using in silico studies, 2 CCAAT/enhancer binding protein alpha (cEBPα) consensus-binding sites were found to be 100% conserved in mouse, rat, and hPit1 promoters. Deletion of 1 cEBPα site prevented the RET-induced increase in hPit1 promoter expression. TaqMan qRT-PCR (real time RT-PCR) for RET, Pit1, Arf, TP53, GDNF, steroidogenic factor 1, and GH was performed in RNA from whole ACRO and NFPA tumors. ACRO but not NFPA adenomas express RET and Pit1. GDNF expression in the tumors was positively correlated with RET and negatively correlated with p53. In conclusion, ACROs maintain an active RET/Pit1/p14Arf/p53/apoptosis pathway that is inhibited by GDNF. Disruption of GDNF's survival function might constitute a new therapeutic route in acromegaly.

scholarly journals ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Farnaz Sedigheh Takhsha ◽  
Christel Vangestel ◽  
Muhammet Tanc ◽  
Sven De Bruycker ◽  
Maya Berg ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Tumor Growth Inhibition ◽  
Beneficial Effects ◽  
Transmission Electron ◽  
Anti Cancer ◽  
The Individual

Resistance against anti-cancer therapy is one of the major challenges during treatment of multiple cancers. Gemcitabine is a standard first-line chemotherapeutic drug, yet autophagy is highly activated in the hypoxic microenvironment of solid tumors and enhances the survival of tumor cells against gemcitabine chemotherapy. Recently, we showed the add-on effect of autophagy inhibitor UAMC-2526 to prevent HT-29 colorectal tumor growth in CD1-/- Foxn1nu mice treated with oxaliplatin. In this study, we aimed to investigate the potential beneficial effects of UAMC-2526 in a syngeneic Panc02 mouse model of pancreatic ductal adenocarcinoma (PDAC). Our data showed that UAMC-2526 combined with gemcitabine significantly reduced tumor growth as compared to the individual treatments. However, in contrast to in vitro experiments with Panc02 cells in culture, we were unable to detect autophagy inhibition by UAMC-2526 in Panc02 tumor tissue, neither via western blot analysis of autophagy markers LC3 and p62, nor by transmission electron microscopy. In vitro experiments revealed that UAMC-2526 enhances the potential of gemcitabine to inhibit Panc02 cell proliferation without obvious induction of cell death. Altogether, we conclude that although the combination treatment of UAMC-2526 with gemcitabine did not inhibit autophagy in the Panc02 mouse model, it has a beneficial effect on tumor growth inhibition.

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