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，一旦转移存活率很低。尽管AJCC 2009 I期黑色素瘤预后良好，但约10%的患者会发展为侵袭性黑色素瘤。纽卡斯尔大学细胞医学研究所的Penny Lovat教授小组已经确定了一组高危AJCC I期肿瘤的标记。该标记集的特征是表皮AMBRA1（一种促自噬调节蛋白，在表皮分化中也很重要）和Loricrin（一种终末表皮分化标记）在原发性黑色素瘤上的表皮中共同缺失。Lovat实验室发现原发性黑色素瘤分泌TGF- β2导致表皮AMBRA1和Loricrin表达下调，内皮中AMBRA1和间隙连接蛋白表达下调，导致内皮完整性丧失和转移。他们证明，在体外内皮细胞系中，非典型TGF-β2介导的AMBRA1下调可以通过siRNA敲低ALK1 （TGF-β家族的内皮I型受体）来阻止。本研究项目的主要目的是进一步验证ALK1作为一种辅助治疗靶点，以防止TGF-β2分泌的高风险早期AJCC期黑色素瘤的转移，并在体外细胞实验中测试一些新的化合物对ALK1的抑制潜力。

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.