pasireotide and Neoplasms

Somatostatin receptors (sstrs) are G-protein-coupled receptors that mediate various physiological effects when activated by the neuropeptide somatostatin or its synthetic analogs. In addition to the well-documented antisecretory effects of sstr(2)-preferential somatostatin analogs octreotide and lanreotide, ligand binding to sstr initiates an inhibitory action on tumor growth. This effect may result from both indirect actions (suppression of growth factors and growth-promoting hormones [e.g., GH/IGF-1 axis] and inhibition of angiogenesis) and direct actions (activation of antigrowth activities [e.g., apoptosis]). As solid tumor cells express multiple sstrs, there is a rationale to evaluate the potential antitumor effects of pasireotide (SOM230), a multireceptor-targeted somatostatin analog with high binding affinity for sstr(1-3) and sstr(5). Pasireotide reduces systemic IGF-1 levels more potently than currently available somatostatin analogs and has been well tolerated in clinical trials.

Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Receptors, Somatostatin; Somatostatin

Cushing's disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing's disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing's disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 (Sstr5) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression.

Topics: Animals; Corticotrophs; Endopeptidases; Endosomal Sorting Complexes Required for Transport; Humans; Mice; Neoplasms; Pituitary ACTH Hypersecretion; Somatostatin; Transcription Factor AP-1; Ubiquitin Thiolesterase

The somatostatin field has been a success story in terms of medicinal chemistry and drug discovery offering a variety of therapeutic opportunities. A rational medicinal chemistry approach capitalising on structure activity relationships has led to the discovery of SOM230, a novel, stable cyclohexapeptide somatostatin analog which exhibits multi-receptor binding to human somatostatin receptor (SSTR) subtypes (SSTR 1-5). Recently, we extended this research utilising the hydroxproline urethane extension of SOM230 for the attachment of the chelators DTPA and DOTA, which enable early diagnosis of SSTR positive tumors and radiotherapy.

Topics: Chelating Agents; Heterocyclic Compounds, 1-Ring; Humans; Hydroxyproline; Isotope Labeling; Neoplasms; Pentetic Acid; Receptors, Somatostatin; Somatostatin; Technology, Pharmaceutical; Urethane