C205 Activation of the phosphotidylinositol-3 kinase (PI3K) pathway is a common occurrence in many human tumors. In particular, amplifications or activating mutations in the PIK3CA gene (which encodes the catalytic p110α subunit of PI3K), or loss of function/deletion mutations in the gene encoding its antagonist PTEN, have been found with high frequency in a wide range of tumor types. Moreover, dysregulated PI3K pathway signaling is thought to contribute to resistance to a variety of anti-cancer therapies, including genotoxic agents and receptor tyrosine kinase inhibitors.
XL147 is a potent, orally bioavailable inhibitor of the Class I PI3K family of lipid kinases with IC50 values in the nanomolar range in PI3K biochemical assays. XL147 binds in an ATP-competitive and reversible manner, yet is highly selective against a panel of >130 human protein kinases. In cellular assays, XL147 antagonizes the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) resulting in inhibition of phosphorylation of several downstream effectors of PI3K including AKT, ribosomal S6 kinase, and ribosomal S6 protein. Oral administration of XL147 to mice bearing xenografts of MCF-7 breast adenocarcinoma cells (expressing mutationally activated PI3K) or A549 lung adenocarcinoma cells (expressing activated K-Ras and deficient in LKB-1, a tumor suppressor protein negatively regulating the PI3K pathway) results in significant inhibition of tumor PI3K pathway signaling. Treatment with XL147 leads to significant tumor growth inhibition or tumor shrinkage in multiple preclinical cancer models including breast, lung, ovarian and prostate cancers, and gliomas. These effects correlate with inhibition of tumor cell proliferation, inhibition of tumor angiogenesis, and induction of tumor cell apoptosis. Based on these data, XL147 has potential utility as a single agent in tumors where the PI3K pathway is dysregulated. A Phase I dose-escalation study of the safety and pharmacokinetics of XL147 has been initiated in patients with solid tumors. The primary objectives of this study are to evaluate the safety and tolerability of daily oral administration of XL147 and to determine the maximum tolerated dose of XL147 when administered for 21 days followed by 7 days without dosing. Other objectives include evaluation of the pharmacokinetics and pharmacodynamic effects of XL147. Preliminary results from this study will be presented, including available pharmacokinetic and safety data as well as pharmacodynamic analyses of peripheral blood cells and other tissues.