Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells

  • Pituitary. 2021 Jun;24(3):351-358. doi: 10.1007/s11102-020-01113-4.
Thomas Cuny  1 ,  Thomas Graillon  2 ,  Célines Defilles  3 ,  Rakesh Datta  4 ,  Shengwen Zhang  4 ,  Dominique Figarella-Branger  5 ,  Henry Dufour  2 ,  Grégory Mougel  6 ,  Thierry Brue  7 ,  Tanya Landsman  4 ,  Heather A Halem  8 ,  Michael D Culler  8 ,  Anne Barlier  6 ,  Alexandru Saveanu  6
Affiliations
  • 1. Service d'Endocrinologie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, 147 Boulevard Baille, 13005, Marseille, France. [email protected].
  • 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.
PMID: 33433890 DOI: 10.1007/s11102-020-01113-4
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.

Keywords
Acromegaly; Cabergoline; Dopastatin; Octreotide; TBR-065.
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