¹⁸F-FDG microPET imaging detects early transient response to an IGF1R inhibitor in genetically engineered rhabdomyosarcoma models

Background: Alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) are among the most common and most treatment resistant soft tissue sarcomas of childhood. Here, we evaluated the potential of ¹⁸F-Fluorodeoxyglucose (FDG) as a marker of therapeutic response to picropodophyllin (PPP), an IGF1R inhibitor, in a conditional mouse model of ARMS and a conditional model of ERMS/undifferentiated pleomorphic sarcoma (UPS). Procedure: Primary tumor cell cultures from Myf6Cre,Pax3:Fkhr,p53 and Pax7CreER,Ptch1,p53 conditional models of ARMS and ERMS/UPS were found to be highly sensitive to PPP (IC ₅₀ values 150 and 200nM, respectively). Animals of each model were then treated with 80mg/kg/day PPP by intraperitoneal injection for 12 days and imaged by ¹⁸F-FDG microPET. Results: Tumor volumes on day 4 for PPP-treated ARMS and ERMS mice were lower than untreated control mouse tumor volumes, although treated tumors were larger than day 0. However, tumor FDG uptake was significantly reduced on day 4 for PPP-treated mice compared to pretreatment baseline or untreated control mice on day 4 (P<0.05). Nevertheless, by day 12 tumor volumes and FDG uptake for treated mice had increased significantly, indicating rapidly evolving resistance to therapy. Conclusions: ¹⁸F-FDG PET imaging is a potential imaging biomarker of molecular susceptibility to targeted agents early in treatment for this aggressive form of sarcoma, but may find best use serially for Phase I/II studies where chemotherapy and targeted agents are combined to cytoreduce tumors and abrogate Igf1r inhibitor resistance.