Molecular imaging for the quantitative assessment of tumor proliferation, progression and the early assessment of molecular targeted treatment response

Molecular imaging allows for in vivo monitoring of important processes for tumor development, tumor growth and, finally, treatment response. The major goal of this study was to investigate different multi-modal imaging techniques for the assessment of different tumor specific molecular processes (Jacobs et al., 2005a; Ullrich et al., 2008a; Ullrich et al., 2008b). In the first step, I investigated the use of [18F]FLT for the non-invasive in vivo assessment of tumor proliferation in different types of tumor models in men and mice. [18F]FLT reacts as a substrate of thymidinkinase 1 (TK1) that is highly expressed during S-phase of the cell cycle. Shields et al could show that the accumulation of [18F]FLT reflects cells entering the s-phase in vitro and in vivo (Shields et al., 1998). Here, we first sought to analyze the accuracy of [18F]FLT to detect tumor cell proliferation in patients with gliomas. We investigated the dynamic [18F]FLT distribution for the asessment of tumor cell proliferation in vivo (Ullrich et al., 2008a). In patients with newly diagnosed high grade gliomas we showed by the use of kinetic analyses that the phosphorylation rate of [18F]FLT by thymidine kinase 1 can be detected and, most importantly, is related to tumor cell proliferation as in vitro assessed by Ki-67 immunostaining. We concluded that [18F]FLT PET represents an accurate marker for the in vivo assessment of tumor cell proliferation in patients with gliomas. We next hypothesized that [18F]FLT PET might provide a sensitive marker for monitoring treatment induced G1 arrest in Non small cell lung cancer (NSCLC). Herewith, we analyzed [18F]FLT in comparison to [18F]FDG PET as a marker for monitoring anti-proliferative treatment response. In collaboration with the Cancer Genomic Group by Dr. Roman Thomas we investigated the potential of [18F]FLT to detect treatment response to specific Epithelial growth factor receptor (EGFR) inhibition in an EGFR-dependent NSCLC model. We used two EGFR-inhibition sensitive cell lines harboring the L858R mutation leading to oncogenic dependency on EGFR signaling. To validate the specificity of EGFR-inhibition we applied the EGFR inhibition resistant cell line H1975 harboring both the L858R and the T790M mutation. The T790M mutation prevents Erlotinib from binding to the intracellular domain of the EGFR. Only two days after initiation of treatment we observed a striking decrease in [18F]FLT uptake in the EGFR-mutant tumor xenograft due to 6 therapy induced G1 arrest. The specificity of this approach is confirmed by a complete lack of [18F]FLT response in the T790M EGFR-resistant xenografts. Moreover, the reduction of [18F]FLT uptake after 2 days translated into dramatic tumor shrinkage 6 days later (Ullrich et al., 2008c). Together, these data strongly suggest [18F]FLT PET as a robust marker to assess tumor proliferation, to detect induction of G1 arrest and, thus, to detect therapy response at a very early time point. Tumor growth requires new vessel formation as a critical step in tumor progression. In a recent study our group found a significant correlation between the expression of CD31 and [11C]MET uptake in gliomas (Kracht et al., 2003). [11C]MET is transported via the L amino acid transporter that is expressed on endothelial cells suggesting this tracer for imaging angiogenesis. Based on these findings we further investigated the relationship between [11C]MET uptake and angiogenesis during tumor progression by comparing uptake ratios of [11C]MET and the expression of the vascular endothelial growth factor (VEGF) in patients with gliomas. Here, we again found a significant correlation between changes in VEGF expression and [11C]MET uptake (Ullrich et al., 2009). Moreover, increase in [11C]MET uptake of more than 14,6 % was highly sensitive and specific to detect malignant progression in patients with gliomas. In summary, multi-modal imaging enables to assess tumor relevant processes, to monitor changes in tumor growth and, finally, to assess treatment response to agents targeting those processes