Title : Preclinical efficacy of the anti - hepatocyte growth factor antibody

Purpose: Ficlatuzumab is a novel therapeutic agent targeting the hepatocyte growth factor (HGF)/c-MET pathway. We summarize extensive preclinical work using this agent in a mouse brain orthotopic model of glioblastoma. Experimental Design: Sequential experiments were done using 8to 9-week old nude mice injected with 3x10 U87 MG (glioblastoma) cells into the brain. Evaluation of ficlatuzumab dose response for this brain tumor model and comparison of its response to ficlatuzumab and to temozolamide were performed first. Subsequently, various small animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and magnetic resonance imaging (MRI), were used with a U87 MGLuc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to non-invasively assess tumor growth and response to therapy. ANOVA was performed to evaluate for significant differences in the response. Results: There was a survival benefit with ficlatuzumab alone or in combination with temozolamide. BLI was more sensitive than PET in detecting tumor cells. Fluoro-Lthymidine (FLT) PET provided a better signal-to-background ratio than fluorodeoxyglucose (FDG) PET. Additionally, both BLI and FLT PET showed significant changes over time in the control group as well as with response to therapy. MRI does not disclose any time-dependent change. Also, the MRI results showed a temporal delay in comparison to the BLI and FLT PET findings, showing similar results one drug cycle later. Conclusions: Targeting the (HGF)/c-MET pathway with the novel agent ficlatuzumab appears promising for the treatment of glioblastoma. Various clinically applicable imaging modalities including FLT, PET, and MRI provide reliable ways of assessing tumor growth and response to therapy. Given the clinical applicability of these findings, future studies on patients with glioblastoma may be appropriate. Research. on April 14, 2017. © 2013 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 27, 2013; DOI: 10.1158/1078-0432.CCR-12-1015