Development and evaluation of biological reagents targeting and inhibiting function of the EphA3 receptor on tumor cells

肿瘤细胞EphA3受体靶向抑制功能生物试剂的开发与评价

• 批准号: nhmrc : 234707
• 负责人: A/Pr Martin Lackmann
• 金额: $ 32.71万
• 依托单位: Monash University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/development-evaluation-biological-tumor-cells/101431
• 关键词: Development; evaluation; biological; reagents; targeting

Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at high levels in lung, kidney and brain tumours, leukemia and malignant melanoma. High levels of EphA3 and corresponding ligands correlate with melanoma progression, and EphA3 stimulation triggers repulsion and detachment of melanoma cells. It is likely that Eph A3 is involved in release and spreading of tumour cells during melanoma progression. We have characterised reagents, the soluble EphA3 ligand and a monoclonal anti-EphA3 antibody, which bind EphA3 with high affinity and specificity. We will use these two proteins, or modified forms containing attached radiochemicals or cytotoxins, to target human tumours that were implanted into into immuno-deficient mice as animal model system. Our studies will determine if the specificity of our reagents, suggested from previous in-vitro studies, will allow imaging of EphA3 containing tumours, and effect their targeted killing. We will also use a tissue culture model, containing artificial epidermal and dermal layers of skin cells, to study if an inhibitory form of the EphA3 ligand will affect the invasiveness of EphA3 positive, metastatic melanoma cells. Furthermore, we will identify essential parts of this ligand to develop inhibitors with improved pharmacological properties. Together, our studies will establish the role for EphA3 in cancer progression and to assess the efficacy of EphA3 targeting for tumor killing and prevention of metastasis. We envision that this will provide the groundwork for Eph-specific reagents with anti-metastatic action in cancer therapy.

Eph受体及其配体调节胚胎的形态发生；在组织层和器官系统的形成过程中，它们指导细胞的迁移和定位。几乎没有证据表明Ephs在成人组织中具有功能。然而，它们的大量、意外出现在各种恶性肿瘤中，表明它们在癌症中起到了作用。这项建议的主要研究对象人类EphA3在成人组织中没有发现，但在肺、肾和脑肿瘤、白血病和恶性黑色素瘤中含量较高。高水平的EphA3和相应的配体与黑色素瘤的进展相关，EphA3的刺激触发了黑色素瘤细胞的排斥和脱离。EphA3很可能参与了黑色素瘤进展过程中肿瘤细胞的释放和扩散。我们已经鉴定了试剂、可溶性EphA3配体和抗EphA3单抗，它们以高亲和力和特异性结合EphA3。我们将使用这两种蛋白质，或含有附着的放射化学物质或细胞毒素的修饰形式，来靶向植入免疫缺陷小鼠体内的人类肿瘤作为动物模型系统。我们的研究将确定我们的试剂的特异性，根据之前的体外研究，是否可以对含有EphA3的肿瘤进行成像，并实现它们的靶向杀伤。我们还将使用包含人造皮肤细胞的表皮和真皮层的组织培养模型来研究EphA3配体的抑制形式是否会影响EphA3阳性的转移性黑色素瘤细胞的侵袭力。此外，我们将确定该配体的必要部分，以开发具有更好药理特性的抑制剂。总之，我们的研究将确定EphA3在癌症进展中的作用，并评估EphA3靶向治疗肿瘤和预防转移的有效性。我们预计这将为Eph特异性试剂在癌症治疗中的抗转移作用提供基础。