Targeting Ligand-Dependent BMP Signaling in Melanoma
Abstract
The studies in this project seek to understand the role of bone morphogenetic protein (BMP) signaling in melanoma and develop a treatment to target ligand-dependent BMP signaling. From previous studies we know that BMP signaling represses MITF expression and upregulates expression of neural crest genes, imparting a less-differentiated neural crest-like identity to melanoma cells. Inhibition of BMP signaling causes melanoma cells to express differentiation genes and die, preventing outgrowth of xenografted tumors. To target BMP signaling, we have created monoclonal antibodies that neutralize the BMP ligand GDF6. The GDF6 gene is copy number amplified in melanoma cells, and elevated expression of GDF6 is associated with a dependence of melanoma cells on BMP activity. Preliminary results suggest anti-GDF6 monoclonal antibodies effectively inhibit BMP signaling, blocking growth and causing death of melanoma cells. We will test if these antibodies shrink xenografted tumors and determine their effects on melanoma cells. We will also determine if the most effective of these antibodies complements existing melanoma therapies in shrinking melanoma xenografts. Additionally, the presence of BMP signaling in rare acral and mucosal melanoma subtypes will be determined, and, should BMP signaling be prevalent, the dependence of these subtypes on GDF6 will be tested in vitro and in xenograft studies. This combination of experiments will determine if the BMP activity that is evident in a majority of melanomas can be targeted as a monotherapy, in combination with existing therapies and as a treatment for rare acral and mucosal melanoma subtypes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2022
- Accession Number
- AD1191593
Entities
People
- Craig J Ceol
Organizations
- University of Massachusetts Medical School