Evaluating the therapeutic potential of ALK1 inhibition to prevent invasion and metastasis of TGF-β2 secreting melanomas.

黑色素瘤是最具侵袭性的皮肤癌，一旦转移存活率极低。纽卡斯尔大学细胞医学研究所的Penny Lovat教授团队已经确定了一组高危AJCC I期肿瘤的标志物，尽管AJCC 2009期黑色素瘤预后良好，但约10%的黑色素瘤会进展并成为侵袭性肿瘤。这一标志物的特征是在原发黑色素瘤上的表皮中，表皮AMBRA1(一种促进自噬的调节蛋白，在表皮分化中也很重要)和Loricrin(终末表皮分化的标志物)的共同缺失。洛瓦特实验室发现，原发黑色素瘤分泌转化生长因子-β2导致表皮中AMBRA1和Loricrin的下调，以及内皮中AMBRA1和缝隙连接蛋白的表达下调，从而导致内皮完整性丧失和转移。这项研究的主要目的是进一步验证ALK1作为辅助治疗靶点来预防早期恶性黑色素瘤的转移，特别是通过体外细胞实验测试一些新化合物对ALK1的抑制作用。

Melanoma it is the most aggressive skin cancer with significant low survival rates once it metastasizes. Even though AJCC 2009 stage I melanoma have a good prognosis, ~10% of them will progress and become invasive.The group of Professor Penny Lovat at the Institute of Cellular Medicine, Newcastle University has identified a marker set for high-risk AJCC stage I tumours. This marker set is characterized by the combined loss of epidermal AMBRA1 (a pro-autophagy regulatory protein also important in epidermal differentiation) and Loricrin (a marker of terminal epidermal differentiation) in the epidermis overlying primary melanomas.The Lovat lab showed that secretion of TGF- β2 by primary melanomas leads to the down regulation of AMBRA1 and Loricrin in the epidermis as well as the down regulation of AMBRA1 and gap junctional protein expression in the endothelium inducing loss of endothelial integrity and metastasis. They demonstrated that non-canonical TGF-β2-mediated down-regulation of AMBRA1 can be prevented by siRNA knockdown of ALK1, an endothelial type I receptor of the TGF-β family, in vitro in endothelial cell lines.The principle aim of the current research project is to further validate ALK1 as an adjuvant therapeutic target to prevent metastasis of TGF-β2 secreting high risk early AJCC stage melanomas, and specifically to test a number of novel compounds for their potential to inhibit ALK1 in in vitro cell based assays.