The objective of the proposed research is to characterize a monoclonal antibody (mAb) that binds and blocks Fibroblast Growth Factor 2 (FGF2) for potential use in cancer therapy. The FGF family of growth factors is a large group of factors believed to play a role in the growth of many tumors, as well as in aspects of normal development. In particular, FGF2 (basic FGF) not only stimulates some tumor cells directly, but is a powerful inducer of angiogenesis, the new blood vessel formation needed by tumors to grow. Overexpression of FGF2 and/or correlation of FGF2 level with clinical features or outcome has been reported for melanoma, prostate cancer, pancreatic cancer, liver cancer (hepatoma), esophageal cancer, thyroid carcinoma and other types of cancer. The Applicant has already generated an anti-FGF2 mAb and in preliminary studies shown that it binds a different epitope than other anti-FGF2 mAbs, blocks a bioactivity of FGF2 and, importantly, strongly inhibits growth of a hepatoma tumor xenograft. In the proposed research plan, this anti-FGF2 mAb, designated GAL-F2, will be intensively studied both in vitro and in vivo, in order to provide the scientific justification for moving it toward clinical trials. The ability of GAL-F2 to bind to various forms of FGF2 and to block binding of FGF2 to the four FGF receptors, FGFR1-4, will be determined. The ability of GAL-F2 to inhibit FGF2- induced cell proliferation and migration, and to inhibit soft agar colony formation by human hepatoma cell lines, will be investigated. Another important aim will be to show that GAL-F2 has potent anti-angiogenic properties, for example by showing that the mAb inhibits blood vessel formation induced by xenografts of a highly angiogenic retinoblastoma cell line. Finally, experiments will be conducted to investigate the capability of the GAL-F2 mAb to block growth of human hepatoma tumor xenografts in mouse models; the results will be critical for the potential choice of hepatocellular carcinoma as the initial clinical indication for the mAb. It is expected that in Phase II of this grant proposal, more extensive animal model and mechanism of action studies will be conducted, and the GAL-F2 mAb will be converted into a humanized antibody suitable for clinical development.
Public Health Relevance: Despite recent scientific advances, cancer remains a major medical problem. The objective of the planned program is to study a monoclonal antibody that targets a growth factor believed to be involved in many tumors. The antibody has the potential to be an effective drug for various types of cancer including liver, pancreatic, and prostate.
Thesaurus Terms: Atp[{..}]protein-Tyrosine O-Phosphotransferase; Advanced Cancer; Advanced Malignant Neoplasm; Agar; Angiogenesis Inducers; Angiogenesis Inducing Agents; Angiogenesis Stimulating Agents; Angiogenesis Stimulators; Animal Model; Animal Models And Related Studies; Anti-Vegf; Anti-Vegf Humanized Monoclonal Antibody; Anti-Vegf Rhumab; Antibodies; Antigenic Determinants; Applications Grants; Assay; Basic Fibroblast Growth Factor Overexpression; Bevacizumab (Rhumab Vegf); Binding; Binding (Molecular Function); Binding Determinants; Bioassay; Biologic Assays; Biological Assay; Blood Vessels; Cancer Treatment; Cancer Of Prostate; Cancer Of The Esophagus; Carcinoma Of The Liver Cells; Carcinoma Of The Thyroid Gland; Cell Communication And Signaling; Cell Growth In Number; Cell Line; Cell Lines, Strains; Cell Multiplication; Cell Proliferation; Cell Signaling; Cellline; Cellular Proliferation; Clinical; Clinical Trials; Clinical Trials, Unspecified; Dna Synthesis Factor; Development; Drugs; Ecgf; Eph- And Elk-Related Tyrosine Kinase; Eph-And Elk-Related Kinase; Epha8; Endothelial Cell Growth Factor; Epha8 Protein; Ephrin Type-A Receptor 8; Ephrin Type-A Receptor 8 Precursor; Epitopes; Esophageal Cancer; Esophagus Cancer; Fgf; Fgf-2; Fgf-R; Fgf2; Fgfr; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor 2 Overexpression; Fibroblast Growth Factor Receptor Family; Fibroblast Growth Factor Receptors; Fibroblast Growth Factor, Basic; Fibroblast Growth Regulatory Factor; Gfac; Gastrointestinal Tract, Pancreas; Generalized Growth; Genital System, Male, Prostate; Goals; Grant; Grant Proposals; Grants, Applications; Growth; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Hbgf; Hbgf-2; Hcc; Hek3; Head And Neck Cancer, Thyroid; Heparin-Binding Growth Factor 2; Heparin-Binding Growth Factor Class Ii; Hepatic Cancer; Hepatocellular Carcinoma; Hepatocellular Cancer; Hepatoma; Heterograft; Human; Human Prostate; Human Prostate Gland; Human, General; In Vitro; Intracellular Communication And Signaling; Liver; Malignant Esophageal Neoplasm; Malignant Esophageal Tumor; Malignant Melanoma; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Pancreatic Neoplasm; Malignant Tumor Of The Esophagus; Malignant Tumor Of The Prostate; Malignant Neoplasm Of Esophagus; Malignant Neoplasm Of Liver; Malignant Neoplasm Of Pancreas; Malignant Neoplasm Of Prostate; Malignant Prostatic Tumor; Man (Taxonomy); Man, Modern; Medical; Medication; Moab Vegf; Moab, Clinical Treatment; Molecular Interaction; Monoclonal Antibodies; Monoclonal Antibody Anti-Vegf; Neuroblastoma Of The Retina; Neuroblastoma, Retinal; Nexavar; Outcome; Ptk; Pancreas; Pancreas Cancer; Pancreatic; Pancreatic Cancer; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Play; Primary Carcinoma Of The Liver Cells; Programs (Pt); Programs [publication Type]; Property; Property, Loinc Axis 2; Prostate; Prostate Ca; Prostate Cancer; Prostate Epithelial Cell Growth Factor; Prostate Gland; Prostatic Cancer; Prostatic Gland; Prostatropin; Protein Tyrosine Kinase; Protein Tyrosine Kinase Eek; Receptor Protein; Receptors, Fgf; Recombinant Humanized Anti-Vegf Monoclonal Antibody; Recombinant Humanized Monoclonal Antibody To Vascular Endothelial Growth Factor; Reporting; Research; Retinoblastoma; Rhumab Vegf; Role; Scientific Advances And Accomplishments; Signal Transduction; Signal Transduction Systems; Signaling; System; System, Loinc Axis 4; Testing; Therapeutic; Thyroid Cancer; Thyroid Carcinoma; Tissue Growth; Transplantation, Heterologous; Tumor Cell; Tyrosine Kinase; Tyrosine-Protein Kinase Receptor Eek; Tyrosine-Specific Protein Kinase; Tyrosylprotein Kinase; Xenograft; Xenograft Model; Xenograft Procedure; Xenotransplantation; Anticancer Therapy; Bfgf; Bfgf Overexpression; Bevacizumab; Biological Signal Transduction; Body System, Hepatic; Cancer Therapy; Cancer Type; Clinical Investigation; Cultured Cell Line; Drug/Agent; Experiment; Experimental Research; Experimental Study; Hepatoma Cell; Humanized Antibody; Hydroxyaryl Protein Kinase; In Vitro Assay; In Vivo; Liver Cancer; Malignant Liver Tumor; Melanoma; Migration; Model Organism; Mouse Model; Neoplastic; Neoplastic Cell; Ontogeny; Organ System, Hepatic; Programs; Public Health Relevance; Receptor; Research Study; Rhumabvegf; Scientific Accomplishments; Scientific Advances; Small Molecule; Social Role; Tumor; Tumor Xenograft; Tyrosyl Protein Kinase; Vascular
