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

• Applicant: Ioana Cosgarea
• Subject Area: Dermatology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396161410

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.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professorin Penny Lovat