Monoclonal Antibody to FGF2 for Treatment of Hepatocellular Carcinoma and Other C

描述(由申请人提供)：拟议研究的目标是表征一种结合和阻断成纤维细胞生长因子2(FGF2)的单抗，以用于癌症治疗。成纤维细胞生长因子家族是一大类被认为在许多肿瘤的生长和正常发育方面发挥作用的因子。特别是，FGF2(碱性成纤维细胞生长因子)不仅直接刺激一些肿瘤细胞，而且是血管生成的强大诱导剂，血管生成是肿瘤生长所需的新血管形成。据报道，在黑色素瘤、前列腺癌、胰腺癌、肝癌、食道癌、甲状腺癌和其他类型的癌症中，FGF2过表达和/或FGF2水平与临床特征或预后相关。申请人已经产生了一种抗FGF2单抗，初步研究表明，它与其他抗FGF2单抗结合的表位不同，阻断了FGF2的生物活性，重要的是，它强烈抑制了肝癌异种移植瘤的生长。在拟议的研究计划中，这种名为GAL-F2的抗FGF2单抗将在体外和体内进行深入的研究，以便为将其推向临床试验提供科学依据。GAL-F2与不同形式的FGF2结合的能力以及阻断FGF2与四种成纤维细胞生长因子受体FGFR1-4的结合的能力将被确定。GAL-F2抑制FGF2诱导的细胞增殖和迁移的能力，以及抑制人肝癌细胞系软琼脂克隆形成的能力，将被研究。另一个重要的目的是证明Gal-F2具有强大的抗血管生成特性，例如，通过显示mAb抑制由高血管生成的视网膜母细胞瘤细胞系异种移植诱导的血管形成。最后，将通过实验研究Gal-F2单抗在小鼠模型中阻断人肝癌移植瘤生长的能力；这一结果将对选择肝细胞癌作为单抗的初步临床适应症至关重要。预计在这项拨款建议的第二阶段，将进行更广泛的动物模型和作用机制研究，并将Gal-F2单抗转化为适合临床开发的人源化抗体。 公共卫生相关性：尽管最近取得了科学进展，但癌症仍然是一个主要的医学问题。这项计划的目标是研究一种针对生长因子的单抗，据信这种生长因子与许多肿瘤有关。该抗体有可能成为治疗包括肝癌、胰腺癌和前列腺癌在内的各种癌症的有效药物。

DESCRIPTION (provided by applicant): 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.