Pharmacology. Cabozantinib is a multi-targeted inhibitor of RTKs. The targets of cabozantinib include several RTKs known to play important roles in tumor cell proliferation and/or tumor neovascularization, namely VEGFR2 (also known as KDR), MET, AXL, and RET. Other recognized targets of cabozantinib include ROS1, XXXX, XXXX, XXX0, XXXX0, and MER, two additional members of the VEGFR family (VEGFR1, VEGFR3), and the closely related RTKs KIT and FLT3. The mode of action for cabozantinib is similar to other drugs targeting RTKs: binding in a fully reversible manner to a region of the kinase domain (including the ATP-binding site) which forces the kinase activation loop into a pseudo-inactive conformation, thereby inhibiting subsequent catalytic activity (1). The cell-based target inhibition profile of cabozantinib is shown in Table 1. The concentrations associated with 50% inhibition (IC50) in biochemical kinase assays (Table 2) do not always translate evenly in vivo. For example, cabozantinib exhibits comparable potency against MET and VEGFR2 in cellular and in vivo assays, in spite of its apparent greater potency for inhibition of VEGFR2 in biochemical kinase assays. Data from pharmacodynamic experiments have shown that cabozantinib inhibits MET and VEGFR2 in vivo. Oral administration of cabozantinib resulted in blockade of MET phosphorylation in human lung tumor xenografts grown in nude mice, blockade of MET phosphorylation in livers of mice, and blockade of VEGFR2 phosphorylation in mouse lung tissue. For both targets, the duration of action for cabozantinib was sustained, with > 50% inhibition observed for > 8 h post-dose at a single dose level of 100 mg/kg (2). In addition, oral administration of cabozantinib resulted in blockade of phosphorylation of mutationally activated RET in TT human MTC xenografts grown in nude mice (1). Treatment with cabozantinib results in anti-angiogenic effects in xenograft tumors, with disruption of the vasculature beginning within 24 h after administration, and is associated with pro- apoptotic effects. These effects translate into significant tumor growth inhibition or tumor regression after cabozantinib treatment in multiple tumor models including MTC, breast cancer, lung carcinoma, and glioblastoma (1,2). IC50, concentration associated with 50% inhibition; MTC, medullary thyroid cancer; SEM, standard error of the mean. a Most frequent somatic mutation in MTC; associated with poor prognosis (3). In preclinical NET models, cabozantinib ...
Pharmacology. Lanreotide is a well-established peptide analogue of the natural hormone somatostatin, in which the biochemical stability of the peptide has been increased by incorporation of modified amino acids. Like native somatostatin, lanreotide inhibits the secretion of many hormones and has anti- proliferative activity (8). Receptors for somatostatin are expressed on the surface of most NETs, and since somatostatin inhibits cell proliferation, the compound can also be used to treat these tumors. The therapeutic use of somatostatin is, however, limited by its short half-life of only 2 to 3 minutes. Therefore, synthetic SSAs with increased specificity and half-life duration have been developed for medicinal use. Lanreotide is a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin. The compound is characterised by the presence of D-Tryptophan in the amino acid ring, increasing stability, and by the presence of D-beta Nal outside of this ring, which increases its selectivity. The terminal amine function reduces binding to central nervous system receptors. Lanreotide exhibits high affinity for the somatostatin Type 2 (SSTR2) and Type 5 (SSTR5) receptors found in the pituitary gland, GH secreting pituitary tumors, NETs and the digestive tract. The product has a much lower affinity for somatostatin Type 1, 3 and 4 receptors (8). Activity at human SSTR2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine, and paracrine functions. The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels. In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Lanreotide, plasma GH levels fall rapidly and are maintained for at least 28 days. Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in postprandial insulin secretion, resulting in transient, mild glucose intolerance. Lanreotide inhibits meal-stimulated pancreatic secretions, reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity. Lanreotide has been shown to inhibi...