Preclinical efficacy of the anti-hepatocyte growth factor antibody ficlatuzumab in a mouse brain orthotopic glioma model evaluated by bioluminescence, PET, and MRI

Erik Mittra, Hua Fan-Minogue, Frank I. Lin, Jason Karamchandani, Venkataraman Sriram, May Han, Sanjiv S. Gambhir

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5711-5721
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number20
DOIs
StatePublished - Oct 15 2013
Externally publishedYes

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Hepatocyte Growth Factor
Glioma
Positron-Emission Tomography
Glioblastoma
Antibodies
Brain
Thymidine
Therapeutics
Neoplasms
Fluorodeoxyglucose F18
Growth
ficlatuzumab
Nude Mice
Brain Neoplasms
Analysis of Variance
Research Design
Cell Line
Control Groups
Survival
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Preclinical efficacy of the anti-hepatocyte growth factor antibody ficlatuzumab in a mouse brain orthotopic glioma model evaluated by bioluminescence, PET, and MRI. / Mittra, Erik; Fan-Minogue, Hua; Lin, Frank I.; Karamchandani, Jason; Sriram, Venkataraman; Han, May; Gambhir, Sanjiv S.

In: Clinical Cancer Research, Vol. 19, No. 20, 15.10.2013, p. 5711-5721.

Research output: Contribution to journalArticle

Mittra, Erik ; Fan-Minogue, Hua ; Lin, Frank I. ; Karamchandani, Jason ; Sriram, Venkataraman ; Han, May ; Gambhir, Sanjiv S. / Preclinical efficacy of the anti-hepatocyte growth factor antibody ficlatuzumab in a mouse brain orthotopic glioma model evaluated by bioluminescence, PET, and MRI. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 20. pp. 5711-5721.
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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.",
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AU - Karamchandani, Jason

AU - Sriram, Venkataraman

AU - Han, May

AU - Gambhir, Sanjiv S.

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