Abstract A44: 18F-FLT, a potential biomarker for predicting the synergistic combination of PI3K inhibitor BAY 80-6946* and MEK inhibitor BAY 86-9766.
Authors: Berndorff Dietmar , Mueller Andre Mueller , Haegebarth Andrea , Berndt Mathias , Scholz Arne Scholz , Puehler Florian , Liu Ningshu 
Published: June 2012

Signaling pathways of particular interest in the cancer field are the RAS-RAF-MEK and PI3K-AKT pathways that act as parallel conduits to transduce signals involved in tumor cell proliferation, survival, and cell migration. Compared to targeting either pathway separately, simultaneous inhibition of these two key pathways has been considered to have greater therapeutic efficacy and broader applicability for the treatment of cancers. One of the challenges is the discovery of biomarkers that correlate with efficacy and synergy of PI3K and MEK combination therapy in early-stage clinical trials. To identify the best imaging tracer for monitoring the synergistic anti-tumor activity of BAY 80-6946* and BAY 86-9766, we first compared FDG and FLT uptake in vitro in 2 colorectal (CRC) and 2 non-small cell lung cancer (NSCLC) cell lines bearing either KRAS or KRAS plus PIK3CA mutations. Partial inhibition of FDG- and FLT-uptake (&lt;50%) was observed in tumor cells treated with each agent, while synergistic and complete inhibition of FLT-uptake (&gt;94%) was demonstrated in the combination group. Interestingly, the maximum inhibition of FDG-uptake was much weaker compared to FLT-uptake, indicating that FLT might be a better tracer for PI3K and MEK combination therapy. Further investigation iwas conducted in HCT116 CRC xenografts in mice and H460 NSCLC xenografts in rats. BAY 80-6946* was administered intraveneously (Q2D) at 14 mg/kg in mice and at 3 mg/kg in rats whereas BAY 86-9766 was dosed orally (QD) at 25 mg/kg in mice and at 15 mg/kg in rats. Tumor uptake of 18F-FLT was investigated by PET imaging as well as by quantitative biodistribution 1 day before and 1 day after treatment start. In both models, 18F-FLT tumor uptake was not significantly altered in animals treated with each single agent. However, one day after the treatment in the combination group, 18F-FLT tumor uptake was reduced from 8.50±0.99 %ID/g to 3.91±0.66 %ID/g (n=5, vs vehicle, p&lt;0.05) in HCT116 bearing mice and from 0.91±0.27 %ID/g to 0.31±0.04 %ID/g (n=5, vs vehicle, p&lt;0.05) in H460 bearing rats. Inhibition of 18F-FLT uptake in tumors ocurred before any significant reduction in tumor volume and correlates with tumor growth inhibition assessed by the tumor size at the later time points. Further detailed molecular mechanism on the synergistic inhibition of 18F-FLT uptake by combination of PI3K and MEK inhibitors will be presented. In conclusion, 18F-FLT might be a non-invasive PET imaging tracer that, when used serially ealy in treatment, may predict clinical efficacy and combination synergy of PI3K and MEK inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A44.