Abstract 2797: AMG 511, a potent and selective class I PI3K inhibitor, demonstrates anti-tumor activity in multiple xenograft models
Authors: Zhang Nancy , Caenepeel Sean , Wang Ling , Norman Mark , Kendall Richard , Burgess Terri , Radinsky Robert , Hughes Paul , Freeman Daniel J. 
Published: August 2012

Abstract
Background: Constitutive activation of the phosphoinositide 3-kinases (PI3K) signaling pathway is a frequent event in many cancers and results in increased cell growth and survival. Therefore, PI3K is an attractive target for oncology. This study evaluated the correlation between the pharmacokinetics (PK) and pharmacodynamics (PD) of AMG 511, a potent and selective class I PI3K inhibitor, and anti-tumor activity in preclinical models of human cancer which harbor mutations in the PI3K pathway. Method: To determine the PD, PK, and efficacy relationship of AMG 511, U87 MG (PTEN null), HCT-116 (PI3K & KRAS mutant), or BT474 (PI3K mutant, HER2 amplified) tumor bearing mice were treated with up to 10 mpk AMG 511 daily by oral gavage. For tumor PD time course and dose response studies, AKT phosphorylation (pAKT) was measured using an electrochemiluminescence detection assay after a single-dose of AMG 511 in U87 MG tumor bearing mice. To determine in vivo efficacy, mice bearing established U87 MG, HCT-116, or BT474 tumors were treated daily and measured 2x/week. The mechanism of action of AMG 511 was determined by examining effects on cell proliferation (BrdU incorporation) and apoptosis (caspase staining) using a combination of immunohistochemistry and flow cytometry analyses of ex-vivo U87 MG xenograft tumors following treatment with AMG 511. Results: Inhibition of pAKT in U87 MG tumor tissue was associated with increased plasma concentration of AMG 511 after a single dose (EC50=59 ng/mL). Treatment with 0.3, 1, and 3 mpk AMG 511 inhibited pAKT in tumor tissue by 39, 81, and 92 %, respectively. Treatment with 10 mpk AMG 511 significantly inhibited pAKT up to 16 hrs (p&lt;0.01). A dose-dependent inhibition of xenograft growth was observed with AMG 511 versus vehicle control in multiple tumor xenograft models with PI3K pathway mutations (p&lt;0.03). Flow cytometry analysis demonstrated that AMG 511 treatment resulted in a dose-dependent decrease of BrdU incorporation in tumor and CD31 positive endothelial cells at peak and trough plasma levels (p&lt;0.05). Immunohistochemical analysis confirmed that AMG 511 treatment induced tumor cell apoptosis as measured by caspase staining in U87 MG tumor samples. Conclusion: AMG 511 is a potent pan-PI3K inhibitor, which has significant anti-tumor activity in human tumor xenograft models which harbor PI3K pathway mutations. Tumor growth inhibition is the result of an increase in AMG 511 exposure, a reduction in PI3K signaling, an inhibition of tumor cell and endothelial cell proliferation and an induction of tumor cell apoptosis. These data together provide evidence for the potential clinical investigation of AMG 511 in patients whose tumors harbor mutations in the PI3K pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2797. doi:1538-7445.AM2012-2797