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

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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.

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Funding

This work was supported by IPSEN research grant, Centre National de la Recherche Scientifique (CNRS UMR 7286), Institut National de la Santé et de la Recherche Médicale (INSERM, UMR 1251) Aix Marseille University, Association pour le Developpement et la Recherche Médicales (ADEREM). The project leading to this publication has received funding from "Excellence Initiative of Aix Marseille University A*Midex-a French "Investissement d'Avenir".

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Authors and Affiliations

  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 & Thierry Brue

  2. Service de Neurochirurgie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Timone, Marseille, France

    Thomas Graillon & Henry Dufour

  3. Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Marseille, France

    Célines Defilles

  4. Ipsen Bioscience (Formers Employees), Cambridge, MA, USA

    Rakesh Datta, Shengwen Zhang & Tanya Landsman

  5. Laboratoire d’Anatomopathologie, Aix Marseille University, APHM, Hôpital de la Timone, Marseille, France

    Dominique Figarella-Branger

  6. Laboratoire de Biologie Moléculaire et Biochimie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, Marseille, France

    Grégory Mougel, Anne Barlier & Alexandru Saveanu

  7. Tiburio Therapeutics, Cambridge, MA, USA

    Heather A. Halem & Michael D. Culler

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  1. Thomas Cuny
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  2. Thomas Graillon
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All authors contributed to the redaction of the manuscript. TC and AS reviewed it. All of the coauthors approved it.

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Correspondence to Thomas Cuny.

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RD, SZ, TL, HH, MC have competing interest related to this study. None of the others authors have conflict of interest related to this study.

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Cuny, T., Graillon, T., Defilles, C. et al. 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 24, 351–358 (2021). https://doi.org/10.1007/s11102-020-01113-4

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