The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.

The Met receptor tyrosine kinase and its ligand,

Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacologic characterization of the pyridopyrimidinone derivative XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (a, b, g, and d) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP 3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects. Mol Cancer Ther; 13(5); 1078-91. Ó2014 AACR.

L-selectin mediates homing of lymphocytes to lymph nodes (LN).Transgenic mice that express rat insulin promoter regulated simian virus 40 Tag (RIP-Tag) develop large, local cancers that metastasize to liver but not LN. To test whether this lack of LN metastases reflects their absence from the circulation, transgenic mice were produced that express Tag (T), L-selectin (L), and Escherichia coli LacZ (Z), in pancreatic ␤ cells. LTZ mice developed insulinomas that specifically had LN metastases; metastasis was blocked by an anti L-selectin mAb. LacZ ؉ tumor cells from these LN homed to secondary LN upon transfer. These results suggest that the highly vascularized islet carcinomas are shedding tumor cells into the bloodstream, which is a necessary but insufficient condition for metastasis to occur; L-selectin can facilitate homing of such tumor cells to LN, resulting in metastasis.M etastatic disease is a significant parameter of tumor progression and the primary determinant of poor prognosis. Bloodborne metastasis is a major pathway by which tumor cells seed additional sites in the body. The bloodborne metastatic process can, in principle, be divided into four steps: (i) invasion of cancer cells that have detached from the primary tumor into the vascular system; (ii) dissemination of tumor cells via the circulatory system; (iii) extravasation of tumor cells at a distinct site; and (iv) establishment of a new tumor at that location. Metastasis has principally been studied by using two types of assays (1, 2): i.v. injection of tumor cells to assess their ability to survive, adhere to blood vessel endothelium, extravasate, and establish tumors; and injection into local tissue (usually s.c.) to assess their capability to metastasize from a primary tumor mass. Neither of these assays accurately mimics the metastatic process of endogenously arising primary tumors. The establishment of metastatic lesions requires not only tumor cell proliferation but also induction of angiogenesis to sustain tumor growth (3). In general, however, it remains unclear which events are rate limiting for metastasis to occur. Are tumor cells frequently shed from tumors undergoing persistent neovascularization? Or is it dissemination via the bloodstream or the ability to extravasate that is limiting? We have sought to address these questions in a transgenic mouse model of endogenous primary multistage carcinogenesis in which metastasis is infrequent. We have done this by producing transgenic mice that express L-selectin on endogenous primary insulinomas and then asking whether the frequency of metastasis is affected.RIP-Tag transgenic mice develop islet cell carcinomas as a result of the simian virus 40 Tag oncogene expression in islet ␤ cells (4). Tumor development proceeds through a series of well defined stages, which include: a dysplasia͞carcinoma in situ-like stage, an angiogenic islet stage (5, 6), the solid tumor stage, in which tumors vary in regard to their size and apoptotic incidence (7), and an invasive carcinoma stage (6-8). Metastas...