TBR-065

Introduction: Somatostatin and dopamine (DA) receptors have a pivotal role in controlling hormone secretion and cell proliferation in different neuroendocrine neoplasms, including medullary thyroid cancer (MTC). In the present preclinical study, we evaluated the anti-tumor activity of TBR-065 (formerly BIM-23B065), a second-generation somatostatin-DA chimera, in 2 human MTC cell lines. Methods: The effects of lanreotide (LAN) and TBR-065 on cell growth and proliferation, calcitonin (CT) secretion, cell cycle, apoptosis, cell migration, and tumor-induced angiogenesis have been evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA flow cytometry with propidium iodide (PI), Annexin V-FITC/PI staining, electrochemiluminescence immuno assay, wound-healing assay, and zebrafish platform, respectively. Results: TBR-065 exerted a more prominent anti-tumor activity than LAN in both MTC cell lines, as shown by inhibition of cell proliferation (maximal inhibition in TT: −50.3 and −37.6%, respectively; in MZ-CRC-1: −58.8 and −27%, respectively) and migration (in TT: −42.7 and −22.9%, respectively; in MZ-CRC-1: −75.5 and −58.2%, respectively). Only the new chimera decreased significantly the fraction of cells in S phase (TT: −33.8%; MZ-CRC-1: −18.8%) and increased cells in G2/M phase (TT: +13%; MZ-CRC-1: +30.5%). In addition, TBR-065 exerted a more prominent pro-apoptotic effect than LAN in TT cells. A concomitant decrease in CT secretion was observed after 2 days of incubation with both drugs, with a more relevant effect of TBR-065. However, neither LAN nor TBR-065 showed any effect on tumor-induced angiogenesis, as evaluated using a zebrafish/tumor xenograft model. Discussion/Conclusion: In MTC cell lines, a second-generation somatostatin-DA analog, TBR-065, exerts a more relevant anti-tumor activity than LAN, through modulation of cell cycle, induction of apoptosis, and reduction in migration. Further studies are required to establish whether TBR-065 has comparable potent inhibitory effects on tumor growth in vivo.

A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release. During treatment with BIM23B065, growth hormone secretion was significantly reduced (maximal effect [EMAX] = − 64.8%) with significant reductions in the pulse frequency in two out of three multiple ascending dose cohorts. A circadian component in prolactin secretion was identified, modelled using a combination of two cosine functions with 24 h and 12 h periods. Dosing of BIM23B065 strongly inhibited (EMAX = − 91%) the prolactin release and demonstrated further reduction of prolactin secretion after multiple days of dosing. This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions of BIM23B065.