Thomas Cuny1, Thomas Graillon2, Célines Defilles3, Rakesh Datta4, Shengwen Zhang4, Dominique Figarella-Branger5, Henry Dufour2, Grégory Mougel6, Thierry Brue7, Tanya Landsman4, Heather A Halem8, Michael D Culler8, Anne Barlier6, Alexandru Saveanu6. 1. Service d'Endocrinologie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, 147 Boulevard Baille, 13005, Marseille, France. thomas.cuny@ap-hm.fr. 2. Service de Neurochirurgie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Timone, Marseille, France. 3. Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Marseille, France. 4. Ipsen Bioscience (Formers Employees), Cambridge, MA, USA. 5. Laboratoire d'Anatomopathologie, Aix Marseille University, APHM, Hôpital de la Timone, Marseille, France. 6. Laboratoire de Biologie Moléculaire et Biochimie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, Marseille, France. 7. Service d'Endocrinologie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, 147 Boulevard Baille, 13005, Marseille, France. 8. Tiburio Therapeutics, Cambridge, MA, USA.
Abstract
CONTEXT: Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined). OBJECTIVE: To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas. DESIGN: We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures. METHODS: 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h. RESULTS: All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (Emax = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (Emax = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065. CONCLUSION: TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.
CONTEXT: Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined). OBJECTIVE: To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas. DESIGN: We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures. METHODS: 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h. RESULTS: All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (Emax = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (Emax = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065. CONCLUSION: TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.
Authors: Annamaria Colao; Ludovica F S Grasso; Andrea Giustina; Shlomo Melmed; Philippe Chanson; Alberto M Pereira; Rosario Pivonello Journal: Nat Rev Dis Primers Date: 2019-03-21 Impact factor: 52.329
Authors: Federico Gatto; Richard A Feelders; Rob van der Pas; Johan M Kros; Marlijn Waaijers; Diana Sprij-Mooij; Sebastian J C M M Neggers; Aart-Jan van der Lelij; Francesco Minuto; Steven W J Lamberts; Wouter W de Herder; Diego Ferone; Leo J Hofland Journal: J Clin Endocrinol Metab Date: 2012-11-01 Impact factor: 5.958
Authors: Eliza B Geer; Roberto Salvatori; Atanaska Elenkova; Maria Fleseriu; Rosario Pivonello; Przemyslaw Witek; Richard A Feelders; Marie Bex; Stina W Borresen; Soraya Puglisi; Beverly M K Biller; Fredric Cohen; Francesca Pecori Giraldi Journal: Pituitary Date: 2020-11-20 Impact factor: 4.107