151 Investigating BMP signaling as a therapeutic target in advanced melanoma

Abstract

Melanoma is the leading cause of skin cancer death in the United States, with a 5-year survival rate of 20% for patients with advanced disease. The development of targeted therapies and immunotherapy has helped improve survival for some patients, but many others still face significant therapeutic challenges, including resistance to therapy and relapse of their disease. Furthermore, our understanding of the steps involved in melanoma initiation and progression is incomplete. We are interested in uncovering factors involved in melanoma initiation and progression with a focus on identifying those key factors that have therapeutic potential. Previously, we identified a novel melanoma oncogene, growth differentiation factor 6 (GDF6), a bone morphogenetic protein (BMP) ligand that promotes melanoma by suppressing differentiation and apoptosis. We have shown that the dedifferentiation effects are mediated by suppression of MITF, the master regulator of melanocyte differentiation, and the anti-apoptotic effects of GDF6 are mediated by suppression of SOX9, a pro-apoptotic factor in melanoma. These results establish GDF6-activated BMP signaling may play a significant role during melanoma progression. Here, we further establish BMP activity impacts melanocyte development and may have therapeutic value in established disease. We find that GDF6 inhibits embryonic melanocyte differentiation from the neural crest, suggesting that its function in melanoma to maintain a dedifferentiated state is a reiteration (or reawakening) of its role in early development. We further identify novel anti-GDF6 therapeutic antibodies that exhibit anti-melanoma activity in vitro, indicating inhibition of GDF6-activated BMP signaling is a potential therapeutic approach for advanced melanoma. Together, these results indicate the importance of GDF6-activated BMP signaling in the development of the melanocyte lineage and melanoma, and provide evidence for targeting BMP signaling as a therapeutic approach in advanced melanoma.