in Mouse Xenograft Models Domain Receptor Tyrosine Kinases with Antitumor Activity OSI-930 : A Novel Selective Inhibitor of Kit and Kinase Insert

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro , the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit–expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930. (Cancer Res 2006; 66(2): 1015-24) Introduction Inhibition of protein kinases has recently emerged as a promising therapeutic approach in many types of human cancer and a variety of agents targeting several different protein kinase family members have now been shown to provide significant clinical benefit in certain indications (1–4). Examples of such molecular targeted therapies include small-molecule inhibitors such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (Tarceva, OSI-774), which was shown to increase patient survival in both non–small-cell lung cancer (5, 6) and pancreatic cancer, and imatinib (Gleevec), which has significant clinical benefit in chronic myelogenous leukemia and gastrointestinal stromal tumors (1, 7). The receptor tyrosine kinases Kit and kinase insert domain receptor (KDR) are closely related members of the split kinase domain subfamily of tyrosine kinases, which also includes plateletderived growth factor receptor (PDGFR) a/PDGFRh and colonystimulating factor-1 receptor (CSF-1R). Inhibition of Kit and KDR in vivo might be expected to result in antitumor effects through two distinct mechanisms in appropriate tumor types; i.e., direct effects on the tumor cell phenotype through inhibition of Kit and indirect effects via disruption of endothelial cell function by inhibition of KDR. Combination of these activitieswithin the samemolecule is predicted to result in more potent activity against a broader range of tumor types than a molecule with inhibitory activity against a single target. There is considerable evidence that expression of mutant alleles encoding constitutively active Kit receptor molecules is a major factor driving tumor growth in mast cell leukemias/mastocytosis and gastrointestinal stromal tumors (8–19). In addition, several reports have highlighted the potential for wild-type Kit to be involved in progression of other tumor types, including small-cell lung cancer (20–25). In such tumors, the proposed mechanism for Kit involvement is the generation of an autocrine/paracrine loop due to coexpression of ligand and receptor within the same tumor cell type. Alternatively, for tumors that express Kit but not stem cell factor, circulating stem cell factor levels may be sufficient to activate the Kit receptor when aberrantly expressed on tumor cells. The tyrosine kinase activity of the receptor tyrosine kinase KDR is thought to be essential for promoting the formation of new blood vessels, both during development and in support of growing solid tumors (26), and is therefore considered a viable target for anticancer therapy. KDR is responsible for the formation, proliferation, and survival of endothelial cells in response to vascular endothelial growth factor (VEGF) ligand family members, and Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). G.M. Wynne is currently at VASTox Group PLC, 91 Milton Park, Abingdon, Oxfordshire, OX14 4RY, United Kingdom. S.L. Winski is currently at Array BioPharma, 3200 Walnut Street, Boulder, CO 80301. A. Franks is currently at AstraZeneca, 4709 Mountain Vista Ct. , Loveland, CO 80537. B. Vulevic is currently at Primary Children’s Medical Center, Ste 1500, 100 North Medical Drive, Salt Lake City, UT 84113. D. Henninger is currently at P&G Pharmaceuticals, DS2-8D3, #1086, 8700 MasonMontgomery Road, Mason, OH 45040. T. Zhang is currently at AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451. D.L. Emerson is currently at Tapestry Pharmaceuticals, 4840 Pearl East Circle, 300W, Boulder, CO 80301-2408. Requests for reprints: Andrew J. Garton, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735. Phone: 631-962-0679; Fax: 631-845-5671; E-mail: agarton@osip.com. I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-05-2873 www.aacrjournals. org 1015 Cancer Res 2006; 66: (2). January 15, 2006 Research Article American Association for Cancer Research Copyright © 2006 on February 23, 2013 cancerres.aacrjournals. org Downloaded from DOI:10.1158/0008-5472.CAN-05-2873