skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography

Journal Article · · Molecules
 [1];  [1];  [2]; ORCiD logo [3]; ORCiD logo [3];  [3];  [1]
  1. Univ. of Iowa, Iowa City (United States). Dept. of Radiology
  2. Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Radiology
  3. Wake Forest Univ., Winston-Salem, NC (United States). Dept. of Regenerative Medicine

Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed to be expressed on glioma cells and within the glioma tumor microenvironment. To understand the utility of targeting FAP in this tumor type, the immuno-PET radiopharmaceutical [89Zr]Zr-Df-Bz-F19 mAb was prepared and Lindmo analysis was used for its in vitro evaluation using the U87MG cell line, which expresses FAP endogenously. Lindmo analysis revealed an association constant (Ka) of 10-8 M-1 and an immunoreactivity of 52%. Biodistribution studies in U87MG tumor-bearing mice revealed increasing radiotracer retention in tumors over time, leading to average tumor-to-muscle ratios of 3.1, 7.3, 7.2, and 8.3 at 2, 24, 48 and 72 h, respectively. Small animal PET corroborated the biodistribution studies; tumor-to-muscle ratios at 2, 24, 48, and 72 h were 2.0, 5.0, 6.1 and 7.8, respectively. Autoradiography demonstrated accumulated activity throughout the interior of FAP+ tumors, while sequential tumor sections stained positively for FAP expression. Conversely, FAP- tissues retained minimal radioactivity and were negative for FAP expression by immunohistochemistry. These results demonstrate FAP as a promising biomarker that may be exploited to diagnose and potentially treat GBM and other neuroepithelial cancers.

Research Organization:
Washington Univ., St. Louis, MO (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
SC0008657
OSTI ID:
1801852
Journal Information:
Molecules, Vol. 25, Issue 16; ISSN 1420-3049
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

References (72)

Fibroblast Activation Protein–Targeted PET/CT with 68 Ga-FAPI for Imaging IgG4-Related Disease: Comparison to 18 F-FDG PET/CT journal June 2020
Cerenkov Luminescence Imaging of Medical Isotopes journal June 2010
The role of heparan sulfate in the glomerular basement membrane journal February 2008
Current Challenges and Opportunities in Treating Glioblastoma journal April 2018
Recent Advances in Zirconium-89 Chelator Development journal March 2018
Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood–tumor barrier disruption journal August 2018
Imaging fibroblast activation protein to monitor therapeutic effects of neutralizing interleukin-22 in collagen-induced arthritis journal January 2018
Functional imaging and endoscopy journal January 2011
Fibroblast activation protein inhibitor (FAPI) PET for diagnostics and advanced targeted radiotherapy in head and neck cancers journal May 2020
Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas journal September 2017
The Role of 68 Ga-FAPI PET/CT for Patients with Malignancies of the Lower Gastrointestinal Tract: First Clinical Experience journal February 2020
Fluorescence and Cerenkov luminescence imaging: Applications in small animal research journal January 2016
Cerenkov luminescence imaging (CLI) for image-guided cancer surgery journal May 2016
Copper Chelation Chemistry and its Role in Copper Radiopharmaceuticals journal January 2007
Fibroblast activation protein increases metastatic potential of fibrosarcoma line HT1080 through upregulation of integrin-mediated signaling pathways journal May 2015
Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma journal August 2016
Identification of Sentinel Lymph Node in Stage I???II Breast Cancer With Lymphoscintigraphy and Surgical Gamma Probe: Comparison of Tc-99m MIBI and Tc-99m Sulfur Colloid journal January 2005
Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89 Zr 4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice journal January 2016
Enhancing tissue permeability with MRI guided preclinical focused ultrasound system in rabbit muscle: From normal tissue to VX2 tumor journal June 2017
Bispecific single-chain diabody-immunoliposomes targeting endoglin (CD105) and fibroblast activation protein (FAP) simultaneously journal March 2015
Harnessing the Power of Radionuclides for Optical Imaging: Cerenkov Luminescence Imaging journal November 2011
Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease journal May 2010
N-terminal modification of immunoglobulin polypeptide chains tagged with isothiocyanato chelates journal September 1990
Targeting the Tumor Microenvironment with Fluorescence-Activatable Bispecific Endoglin/Fibroblast Activation Protein Targeting Liposomes journal April 2020
Selective cytotoxicity of 125I-labeled monoclonal antibody T101 in human malignant T cell lines journal February 1986
A Newly Developed Uroplakin II Antibody With Increased Sensitivity in Urothelial Carcinoma of the Bladder journal July 2014
Expression and role of the cell surface protease seprase/fibroblast activation protein-α (FAP-α) in astroglial tumors journal March 2011
Population Pharmacokinetics of Sibrotuzumab, A Novel Therapeutic Monoclonal Antibody, in Cancer Patients journal January 2004
Population pharmacokinetics of antifibroblast activation protein monoclonal antibody F19 in cancer patients: Short report journal February 2001
68Ga-FAPI PET/CT Improves Therapeutic Strategy by Detecting a Second Primary Malignancy in a Patient With Rectal Cancer journal January 2020
Cerenkov luminescence imaging: physics principles and potential applications in biomedical sciences journal March 2017
68 Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers journal August 2018
Optical Imaging of Ionizing Radiation from Clinical Sources journal September 2016
Activatable bispecific liposomes bearing fibroblast activation protein directed single chain fragment/Trastuzumab deliver encapsulated cargo into the nuclei of tumor cells and the tumor microenvironment simultaneously journal May 2017
Standardized methods for the production of high specific-activity zirconium-89 journal October 2009
Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential journal January 2017
Photodynamic Molecular Beacon Triggered by Fibroblast Activation Protein on Cancer-Associated Fibroblasts for Diagnosis and Treatment of Epithelial Cancers journal January 2009
Remote spatiotemporally controlled and biologically selective permeabilization of blood-brain barrier journal November 2015
Identification of sentinel lymph node in breast cancer by lymphoscintigraphy and surgical gamma probe with peritumoral injection of scintimammographic agent “99mTc MIBI” journal April 2002
Activatable Near-Infrared Fluorescent Probe for In Vivo Imaging of Fibroblast Activation Protein-alpha journal July 2012
Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts. journal June 1994
Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies journal September 2012
Cell-surface glycoproteins of human sarcomas: differential expression in normal and malignant tissues and cultured cells. journal May 1988
Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis journal March 2006
89 Zr-Chloride Can Be Used for Immuno-PET Radiochemistry Without Loss of Antigen Reactivity In Vivo journal November 2018
Design and Development of 99m Tc-Labeled FAPI Tracers for SPECT Imaging and 188 Re Therapy journal March 2020
Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3–Targeted Liposomes journal June 2017
Radiation Dosimetry and Biodistribution of 68 Ga-FAPI-46 PET Imaging in Cancer Patients journal December 2019
Current state of immunotherapy for glioblastoma journal April 2018
Novel Single-Chain Fv′ Formats for the Generation of Immunoliposomes by Site-Directed Coupling journal November 2007
Intraoperative lymphatic mapping and sentinel lymph node biopsy using radioactive tracer in gastric cancer journal November 2005
Fibroblast activation protein and chronic liver disease journal January 2008
Immunotherapy for Glioblastoma: Playing Chess, Not Checkers journal April 2018
Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a 68 Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04 journal August 2019
Innovations in Nuclear Imaging Instrumentation: Cerenkov Imaging journal July 2018
Mediastinal intraoperative radioisotope sentinel lymph node mapping in non-small-cell lung cancer journal January 2005
Single-chain Fv immunoliposomes for the targeting of fibroblast activation protein-expressing tumor stromal cells journal January 2007
68 Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer journal April 2019
Fibroblast activation protein: Purification, epitope mapping and induction by growth factors journal August 1994
Immuno-PET and Immuno-SPECT of Rheumatoid Arthritis with Radiolabeled Anti–Fibroblast Activation Protein Antibody Correlates with Severity of Arthritis journal April 2015
Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms journal September 2015
Preliminary Therapy Evaluation of 225 Ac-DOTA-c(RGDyK) Demonstrates that Cerenkov Radiation Derived from 225 Ac Daughter Decay Can Be Detected by Optical Imaging for In Vivo Tumor Visualization journal January 2016
Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics journal May 2018
Reduction of anionic sites in the glomerular basement membrane by heparanase does not lead to proteinuria journal February 2008
Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64 Cu- and 225 Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models journal October 2019
Targeting fibroblast activation protein in cancer ndash Prospects and caveats journal January 2018
The blood–brain barrier and blood–tumour barrier in brain tumours and metastases journal October 2019
IL13RA2 targeted alpha particle therapy against glioblastomas journal May 2017
Understanding fibroblast activation protein (FAP): Substrates, activities, expression and targeting for cancer therapy journal March 2014
Fibroblast Activation Protein in Remodeling Tissues journal November 2012
Coupled expression of dipeptidyl peptidase-IV and fibroblast activation protein-α in transformed astrocytic cells journal April 2011
Renal FcRn Reclaims Albumin but Facilitates Elimination of IgG journal August 2009