Comparison of [18F]-tracers in various experimental tumor models by PET imaging and identification of an early response biomarker for the novel microtubule stabilizer patupilone.

PURPOSE: The suitability of [18F]FDG, [18F]FLT, [18F]FET, and [18F]FCH as non-invasive positron emission tomography (PET) biomarkers for monitoring response to chemotherapy was analyzed in various experimental tumor models. PROCEDURES: Tracer uptake into three syngeneic rodent tumor models and ten human xenograft models was evaluated using semiquantitative analysis of small-animal PET data. Murine RIF-1 fibrosarcomas and [18F]FLT were selected to monitor the effects of the novel cytotoxic patupilone. RESULTS: Except [18F]FCH, all tracers provided good tumor visualization. Highest [18F]FDG uptake was identified in syngeneic tumors. Xenograft models, however, showed low [18F]FDG SUVs and were better visualized by [18F]FLT. Monitoring the effects of patupilone on [18F]FLT uptake in RIF-1 tumors revealed a significant decrease of tracer uptake after 24 h, which strongly negatively correlated with apoptosis. CONCLUSION: [18F]FLT PET of experimental tumors is a viable complement to [18F]FDG for preclinical drug development. [18F]FLT may be an excellent biomarker for patupilone-induced apoptosis.

Minimally invasive biomarkers for therapy monitoring.

Development of new drugs and optimal application of the drugs currently in use in clinical chemotherapy requires the application of biomarkers. Ideally, these biomarkers would stratify patients so that only those patients likely to respond to a particular therapy receive that therapy. However, that is not always feasible, and an alternative is to make use of early response biomarkers to determine the responding population. In this paper, a number of generic (i.e. not necessarily specific to the action mechanism of the compound) early-response biomarkers are discussed and compared in different models and with three compounds with quite different mechanisms of action: a VEGF-R inhibitor (PTK787), an mTOR inhibitor (RAD001) and a microtubule stabiliser (EPO906). The methods include noninvasive DCE-MRI and PET imaging for measuring tumour vascularity, metabolism and proliferation, as well as the minimally invasive WIN method for measuring tumour interstitial pressure (IFP). The data show that drug-induced changes in IFP (delta IFP) involve mechanism-dependent changes in the tumour vascular architecture, and that delta IFP may be considered a universal generic early-response marker of tumour response to therapy.