Molecular imaging of individual tumor metabolism and early prediction of response to therapy with sorafenib in malignant sarcoma

Objectives Our aim is to characterize the individual tumor metabolism at early stage oftherapy in malignant sarcomas. Besides FDG as marker of tumor cell viability, specific markers of tumor cell proliferation and angiogenesis have been suggested as superior imaging biomarkers for early prediction of therapy response.

Methods SCID mice bearing sarcoma A673 xenotransplants were used for investigation of tumor response after sorafenib treatment. F-18-FLT (FLT), Ga-68-NODAGA (NODAGA) and/or F-18-FDG-PET were performed prior and early after initiation of treatment. Tumor-to-background ratios (TBR) of FLT- and/or NODAGA-PET were compared to FDG-PET. Results were correlated with histopathology and in vitro data comprising cellular uptake, cell cycle related protein expression, cell cycle distribution (BrdU) and apoptosis (Annexin V) assay as well as viability assessment.

Results In vitro experiments show that A673 sarcoma cells were sensitive to the therapy evaluated in this preclinical study. For in vivo studies, tumor volume of sorafenib treated animals showed modest increase of 0.1cm3 (range, 0.02cm3- 0.2cm3, SD=0.09) within the first week, as opposed to a 15-fold increase in control mice. Median TBR of FLT-PET decreased significantly to 30.1% compared to baseline as early as 5d after therapy (range, 11.3 - 53.5%, n=12, p=0.0004). On the other hand, TBR in FDG-PET also showed a significant reduction in tumoral tracer uptake (median TBR 74.6%, range 28.1% - 131.8%, n=12, p=0.02). The reduction of TBR in FLT-PET was significantly more pronounced compared to that in FDG-PET (p<0.001).

Conclusions Compared to FDG-PET, FLT-PET is able to predict response early in the course of therapy. Ongoing studies are intensively carried out to investigate NODAGA- PET for monitoring cancer therapies and FLT-PET for prediction of cellular proliferation changing