Research Project
8198811
DESCRIPTION (provided by applicant): The objective of the proposed research is to thoroughly characterize a humanized monoclonal antibody (mAb) that binds and inhibits human Fibroblast Growth Factor 2 (FGF2;basic FGF) for potential use in cancer therapy. FGF2 can directly stimulate tumor cell proliferation and also induces migration, proliferation and differentiation of endothelial cells, so is a potent angiogenic factor. FGF2 is strongly expressed in most gliomas and in renal cell cancer (RCC), contributes to progression of prostate tumors, and is a factor for the growth of melanomas, but has been most strongly associated with hepatocellular carcinoma (HCC), the predominant form of liver cancer (hepatoma). The Applicant has generated an anti-FGF2 mAb, GAL-F2, and shown that it neutralizes all tested biological activities of FGF2 and, importantly, strongly inhibits the growth of tumor xenografts from three different HCC cell lines. The GAL-F2 mAb has already been humanized to generate HuGAL-F2, a mAb potentially suitable for administration to human patients. Hence, the overall goal of the proposed research plan is to generate a data package of functional assay results, mechanism of action findings, animal model studies and initial safety studies that will support filing of an IND for this humanized mAb. More specifically, the binding affinity of HuGAL-F2 for human and mouse FGF2 will be precisely determined, and assays will be conducted for HuGAL-F2 inhibition of (i) binding of FGF2 to its cellular receptors FGFR1-4, (ii) FGF2-induced phosphorylation and cell proliferation, and (iii) FGF2-induced angiogenesis. The ability of HuGAL-F2 to inhibit growth of xenografts from several HCC and RCC cell lines will be explored extensively. In these studies, HuGAL-F2 will be tested both as a single agent and in combination with other drugs: Nexavar, approved for treatment of HCC and RCC;Sutent, approved for treatment of RCC;and Avastin, currently in clinical trials for HCC. The mechanism of action of HuGAL-F2 against tumor growth will be investigated by measuring cellular proliferation, angiogenesis and apoptosis in xenografts from mice treated with the mAb. To expand the potential indications for HuGAL-F2 to brain cancer, the effectiveness of this mAb in treating orthotopic xenografts generated from glioblastoma (GBM) stem cells will also be investigated, as such xenografts replicate the characteristics of true clinical GBMs with high fidelity. Finally, to advance the humanized mAb toward an IND for clinical trials and to help attract a corporate partner/licensee to sponsor further development, a standard tissue cross-reactivity study and an initial toxicology study in rodents will be performed. PUBLIC HEALTH RELEVANCE: Despite recent scientific advances, cancer remains a major medical problem. The objective of the planned program is to test a monoclonal antibody that targets a growth factor believed to be involved in many tumors. The antibody will have the potential to be an effective drug for various types of cancer including liver, kidney, and brain.
