Proto-oncogene colony stimulating factor 1 receptor (CSF-1R) and related overexpressed genes are promising biomarkers for targeted treatment of GBM. Evidence of CSF-1R as a biomarker of GBM micro-environment is rapidly emerging in various preclinical GBM/glioma tumor models. We propose a novel class of radioligands labeled with fluorine-18 (F18) or carbon-11 (C11) for in vivo positron emission tomography (PET) imaging CSF-1R. The CSF-1R binding affinity and selectivity of the ligands will be tested in vitro with ELISA kits and with cancer cell uptake studies. We will design radioligands that target CSF-1Rs with an expected binding affinity of at least 1 nanomolar, which is suitable for in vivo imaging of CSF-1R in the tumor microenvironment. The best CSF-1R ligand candidates radiolabeled with F18 or C11 will be selected based on optimal radioligand biodistribution, pharmacokinetics, stability, and blood-brain-barrier penetration. Small animal PET/MRI imaging with the selected CSF-1R radioligands will be performed in an orthotopic GBM mouse model that will be correlated with GBM tumor progression by bioluminescence imaging. If the identification and quantification of various cells in the tumor and micro-environment can be achieved after chemo-therapy treatment, CSF-1R multimodality imaging will provide critical information about pro-tumorigenic macrophage infiltration and related tumor vasculogenesis. Our CSF1-R imaging approach, utilizing PET and MR imaging, promises to aid clinicians to better diagnosis of GBM, selecting targeted treatments and monitoring treatment response. In addition, it will benefit researchers in multiple disciplines studying the origin, progression, and treatment of GBM that impacts hundred thousands of people worldwide.

Public Health Relevance

Glioblastoma multiforme (GBM) comprises several molecular subtypes and most therapeutic approaches targeting glioma cells have unfortunately failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs) that depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. Thus, a new noninvasive molecular imaging method to understand the translational potential of CSF-1 receptor (CSF-1R) therapy for inhibiting GBM progression will be developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA205564-02
Application #
9399634
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Menkens, Anne E
Project Start
2017-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304