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XL880 AS MULTIKINASE INHIBITOR

by Selleckchem | Mar 13 2012

XL880: Inhibition of the VEGF-R/KDR/MET pathway

Vascular endothelial growth factor (VEGF) is a signaling protein that is involved in the angiogenesis and vasculogenesis of damaged tissues. Increases in vascular structure are an important part of tumor growth and VEGF is often over-expressed in many forms of cancer. The mechanism of action of VEGF is through binding to the extracellular portion of the transmembrane VEGF receptors which leads to intracellular signaling which control stimulation of endothelial cell mitogenesis, cell migration, increases in vasodilation and .microvascular permeability. Over-expression of VEGF has been linked to poor prognosis in breast cancer, rheumatoid arthritis, diabetic retinopathy, age related macular degeneration and angiosarcoma. Targeting the VRGF signaling pathway is means of controlling tumor growth and metastasis. One of the ways in which this can be achieved is by inhibition of VEGF or VEGFR with small molecules. XL880 is a tyrosine kinase inhibitor which targets hepatocyte growth factor (HGF) and its endothelial receptor (MET). MET and VEGF co-operate to promote vascularization of tumors. Single therapy treatments against the VEGF pathway initially can be extremely effective but can lose effectiveness over time, the suggestion is that the MET pathway offers an escape route for cell survival when VEGF is inhibited. [1]

XL-880 is small molecule inhibitor which targets both the MET and VEFG pathway characterized by a very slow recovery rate. XL-880 binds to the MET receptor preventing phosphorylation, it also binding to VEGF receptors inhibiting extracellular phosphorylation. This double targeting means XL-880 is particularly effective in inhibiting tumor growth even under hypoxic conditions. [2] The MET receptor, the VEGF receptor and their associated ligands have been demonstrated to be over-expressed in many tumor types indicating that XL-880 is potentially a significant step in targeted chemotherapy in comparison to other TKI’s under development.

XL-880: Properties and Availability

XL-880 structure is described as a derivative of dicarboxamide and first developed by Exelixis Inc but is now being developed by GlaxoSmithLine. XL-880 is marketed under the trade name Foretinib and is available in high purity from a limited number of XL-880 suppliers. XL-880 price varies greatly between suppliers ranging from $120 – 200 for a 5 mg vial, to buy XL-880 researchers are advised to shop carefully to obtain the best value for money. For XL-880 stability in solution it is recommended that all stocks be stored at -20°C and freeze/thaw cycles is kept to a minimum. XL-880 solubility is documented as being relatively good in water, alcohol and DMSO for concentrations of 10 mM or more.

XL880: Preclinical Investigation

Preclinical investigations into XL880 determined the XL880 IC50 for MET and KDR inhibition to be 0.4 nM and 0.8 nM, respectively. XL880 has been tested in a variety of different tumor cell lines and demonstrated significant anti-tumor activity[2-4]. It has been report as effective in ovarian cancer [5], pancreatic cancer [6], gastric cancer [7], hepatocellular carcinoma [8] and chronic myelogenous leukemia (CML) [9]. In each case XL880 prevented metastatic properties and in xenogafts decreased tumor volumes, in addition it was observed to halt the change of the tumor from primary stage to invasive stage.[5]

CLINICAL SUCCESS OF XL880:

XL-880 was test in a phase I clinical trial using naïve patients with untreatable metastatic or solid tumors. Escalating doses of oral foretinib were given in eight cohorts over a 5 day period every 14 days to 40 patients. The MTD for XL880 was recommended to be 240 mg per day for 5 days. In total 25 patient exhibited either stable disease or a partial response to treatment with acceptable toxicity which is over a 50% response rate [10]. In three phase one studies XL880 was assessed against advanced solid tumor and advanced solid malignancies, dose escalation demonstrate comparable MTD’s at 240 mg per day and approximately 50% positive response rate was observed for each trial.[10-13] In a phase 2 study with renal carcinoma patients the pharmacokinetics and Toxicity of XL880 was determined to be within acceptable parameters with 79% demonstrateing active anti-tumor responses. [14;15] In a separate clinical trial in adults with squamous cell cancer of the Head and Neck 65% of patients showed stable disease one year into treatment [16]

References

1. Comoglio PM, Giordano S et al. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008; 7(6):504-516.

2. Qian F, Engst S et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2009; 69(20):8009-8016.

3. Bean J, Brennan C et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007; 104(52):20932-20937.

4. Liu L, Greger J et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009; 69(17):6871-6878.

5. Zillhardt M, Park SM et al. Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis. Clin Cancer Res 2011; 17(12):4042-4051.

6. You WK, Sennino B et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res 2011; 71(14):4758-4768.

7. Kataoka Y, Mukohara T et al. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs 2011.

8. Huynh H, Ong R et al. Foretinib demonstrates anti-tumor activity and improves overall survival in preclinical models of hepatocellular carcinoma. Angiogenesis 2011.

9. Dufies M, Jacquel A et al. Mechanism of action of the multikinase inhibitor Foretinib. Cell Cycle 2011; 10(23).

10. Eder JP, Shapiro GI et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res 2010; 16(13):3507-3516.

11. Shapiro GI, Heath E et al. A Phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics of XL880, a VEGFR and MET kinase inhibitor, administered daily to patients (pts) with advanced malignancies. Molecular Cancer Therapeutics 2007; 6(12):3510S-3511S.

12. Eder JP, Appleman L et al. A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs). Journal of Clinical Oncology 2006; 24(18):131S.

13. LoRusso P, Appleman L et al. A phase 1 study of a novel spectrum selective inhibitor (SSKI), XL880, administered orally in patients with advanced solid malignancies. Clinical Cancer Research 2005; 11(24):9025S.

14. Ross RW, Srinivasan R et al. A Phase 2 study of the dual MET/VEGFR2 inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC). Molecular Cancer Therapeutics 2007; 6(12):3511S.

15. LoRusso P, Appleman L et al. Pharmacodynamics (pd) of XL880, a novel spectrum selective kinase inhibitor (SSKI), administered orally to patients (pts) with advanced solid tumors (AST). Ejc Supplements 2006; 4(12):124.

16. Elferink LA, Resto VA. Receptor-tyrosine-kinase-targeted therapies for head and neck cancer. J Signal Transduct 2011; 2011:982879.