Supplementary Figures - PDF file 110K, Supplementary Figure 1. Dose titration curves of ficlatuzumab. The numbers in parenthesis are the median survival in days. Supplementary Figure 2. combination therapy of ficlatuzumab and temozolomide studied in an intracranial U87 MG xenograft mouse model. The numbers in parenthesis are the median survival in days. Supplementary Figure 3. Comparison of U87 MG parental and U87 MG-Luc2 cells showing similarity in in vitro (a) and in vivo (b) characteristics. Supplementary Figure 4. Change in weight (mean � standard deviation) over the course of the experiment in the control, low-dose, and high-dose groups. Results shown are normalized to the baseline value. The p-values shown are the results of the ANOVA for each group. In this case, there were no significant changes in weight
ARTICLE ABSTRACT
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 eight- to nine-week-old nude mice injected with 3 × 105 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 conducted first. Subsequently, various small-animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and MRI, were used with a U87 MG-Luc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to noninvasively assess tumor growth and response to therapy. ANOVA was conducted 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-D-thymidine (FLT) PET provided a better signal-to-background ratio than 2[18F]fluoro-2-deoxy-d-glucose (FDG) PET. In addition, 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. Clin Cancer Res; 19(20); 5711–21. ©2013 AACR.
