Abstract 362: [18F]-FLT Positron Emission Tomography can be used to image the response of sensitive tumours to PI3-Kinase inhibition with the novel agent GDC-0941.

Abstract

Emerging targeted therapeutics are characterised by high efficacy rates in selected patient sub-populations as well as potentially high running costs. This calls for companion diagnostic tools that contribute to the better management of such therapies, in terms of patient selection and monitoring therapeutic response. The Phosphatidylinositide 3-kinase pathway is deregulated in a range of cancers, and several targeted inhibitors are entering the clinic. This study aimed to investigate whether the PET tracer [18F]-FLT is suitable to mark the effect of the novel PI-3K inhibitor GDC-0941 which has entered Phase II clinical trial. Methods Nude mice bearing U87 and HCT116 xenografts were imaged at baseline with [18F]-FLT (10-15MBq per mouse produced using a GE Tracerlab). GDC-0941 or vehicle was then administered at a concentration of 50mg/kg twice daily by gavage and animals were rescanned at acute (∼18h) and chronic (∼186h) timepoints post-therapy. Standard uptake value (SUV)s for tumour uptake were calculated, and tissue was analysed at sacrifice for phospho-AKT. To generate normalised uptake values (NUV)s the SUV [tumour] was divided by the SUV for heart. NUV figures are given for the 100-105min post-injection time interval. Results Growth of U87 xenografts was significantly inhibited by GDC-0941 treatment throughout the course of the study (average growth rate of treated = –1.0±9.3 mm3, control = 69.2±22.1mm3 per day). Growth of HCT116 xenografts was not significantly different between groups (average growth rate of treated = 34.6±15.9 mm3, control =54.8±11.1 mm3 per day). Tumour uptake of [18F]-FLT was significantly reduced in treated animals bearing U87 xenografts at the acute timepoint compared to baseline (NUVmax 2.17 ± 0.38 vs 1.59 ± 0.29, p<0.01), whereas uptake in HCT116 tumours was unchanged. Analysis of the downstream marker phospho-AKT showed that this was decreased in U87, but not HCT116, tumours. Conclusion [18F]-FLT is a strong candidate for the non-invasive measurement of GDC-0941 action. In addition to FLT, we are assessing the performance of a range of other imaging agents, including proprietary tracers, that can potentially bring value in monitoring of PI3-kinase targeting therapies. 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 362. doi:1538-7445.AM2012-362