Development of anti-metastatic and tumour targeting reagents by design of inhibitors to specific Eph/ephrin cell-cell

转移性疾病，特别是恶性黑色素瘤，是一个具有相当全球重要性的健康问题，仅在澳大利亚每年就有1 000例致命的黑色素瘤病例。虽然在预防和早期诊断方面取得了进展，但对于IV期黑色素瘤尚无根治性治疗方法。肿瘤的进展和转移能力的获得主要反映了细胞粘附和细胞运动的失调，而不是增殖和存活。在这种情况下，Eph受体酪氨酸激酶（Ephs）及其膜结合的ephrin配体是细胞粘附和运动的关键介质，并且在转移性肿瘤中明显过表达，而不是原发性（良性）病变5。我们的实验室率先鉴定出epha37，并率先分离出其配体ephrin-A5。EphA3是从急性淋巴母细胞白血病和恶性黑色素瘤患者中分离出来的，其中表达水平升高与转移进展相关。可溶性的、非簇状的Eph和ephrin是Eph活性3的有效抑制剂，为癌症治疗提供了产生特异性药物的机会。我们现在提出一项研究和开发计划，用于epha3特异性药物的开发和生产，用于临床前和临床评估，以进入国内和国际市场。

Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (Ephs) and their membrane-bound ephrin ligands are crucial mediators of cell adhesion and motility and are notably overexpressed in metastatic tumours rather than primary (benign) lesions5. Our laboratories were the first to identify EphA3 7, and one of the first to isolate its ligand, ephrin-A5. EphA3 was isolated from acute lymphoblastoid leukemia and malignant melanoma patients, where increasing expression levels correlate with metastatic progression. Soluble, non-clustered forms of Ephs and ephrins are effective inhibitors of Eph activity 3 and provide opportunities to generate specific drugs for cancer therapy. We now propose a research and development program for the development of EphA3-specific drugs and their production for pre-clinical and clinical evaluation for placement onto a national and international market.