Biomarker development for XL765, a potent and selective oral dual inhibitor of PI3K and mTOR currently being administered to patients in a Phase I clinical trial

B265 Activation of PI3K results in increased formation of the lipid PIP3 from PIP2. This results in recruitment of AKT to the plasma membrane and its subsequent activation. In turn, activation of AKT ultimately leads to activation of mTOR, which phosphorylates p70S6K and 4E-BP, culminating in increased protein translation. In addition, activated AKT exerts pro-survival and other effects via additional signaling pathways. The PI3K pathway is frequently dysregulated in cancer cells and is implicated in multiple aspects of tumor pathobiology, including tumor growth, survival, angiogenesis, and dissemination. In particular, activating mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K (p110α), and/or loss of function/deletion mutations in the gene encoding its antagonist, the PTEN tumor suppressor, have been found in high frequencies over a wide range of tumor types. In addition, resistance to many anticancer agents has been attributed to failure to downregulate PI3K pathway signaling. Current inhibitors of this signaling pathway include rapamycin and related molecules, which specifically inhibit the mTOR/Raptor complex. However, inhibition of mTOR/Raptor can lead to upregulation of PI3K activity, reflecting alleviation of an mTOR/Raptor-dependent negative feedback loop, with consequent activation of AKT-dependent survival pathways.
 XL765 is a selective oral inhibitor of Class I PI3K isoforms and mTOR which exhibits potent inhibitory activity against PI3K pathway signaling in biochemical assays, in cultured cells, and in human xenograft tumors in nude mice. Moreover, administration of XL765 slows tumor growth or causes tumor shrinkage in multiple human xenograft tumor models exhibiting dysregulated PI3K pathway signaling. A series of experiments has been performed to explore baseline PI3K pathway signaling levels and the pharmacodynamic activity of XL765 in various normal human tissue compartments. XL765 inhibited PI3K pathway signaling in a dose-dependent fashion in vitro in peripheral blood cells harvested from the blood of healthy volunteers as assessed by a reduction in phosphorylation of multiple pathway components, including AKT, the AKT substrate PRAS40, p70S6K, and 4E-BP1. Robust PI3K pathway signaling was evident in the bulbs of hair plucked from healthy volunteers. Ex vivo incubation of plucked hair with XL765 resulted in a reduction in phosphorylation of AKT, PRAS40, the p70S6K substrate S6, and 4E-BP1. In addition, ex vivo incubation with XL765 reduced AKT phosphorylation in buccal mucosal smears from healthy volunteers. A Phase I dose-escalation study of the safety and pharmacokinetics of XL765 administered twice daily orally to subjects with solid tumors has been initiated. The primary objectives of this study are to evaluate the safety and tolerability of XL765 and to determine the maximum tolerated dose of XL765 administered twice daily orally for 28 days. Other objectives include evaluation of the pharmacokinetics and pharmacodynamic effects of XL765. 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 using the approaches outlined above.