Research in the Aplin laboratory elucidates mechanisms underlying aberrant growth and invasion in cutaneous melanoma. Melanoma is the deadliest form of skin cancer and its incidence is increasing. It arises from the transformation of melanocytes, the pigment producing cells in the skin. Once melanoma metastasizes, the treatment options are limited; thus, there is an immediate need to understand the mechanisms underlying melanocyte transformation and tumor progression.
The BRAF gene is mutated in half of melanomas. Mutant BRAF promotes melanoma growth and invasion. One focus in the laboratory is determining the effectors of the mutant BRAF that promote malignant traits in melanoma cells. We have identified mechanisms of tumor survival via alterations in the BH-3-only proteins, Bim and Bmf. Additionally, we are investigating the function of Rho family GTPases, epithelial-to-mesenchymal transition transcription factors and integrin-mediated signaling in melanoma cell invasion and migration.
Since 2011, BRAF inhibitors have been FDA-approved for the treatment of advanced mutant BRAF melanoma. Despite eliciting tumor shrinkage in the majority of patients, primary and acquired resistance to these inhibitors is evident. These forms of resistance are major obstacles to the prolonged effects of RAF inhibitor-based therapies. We are elucidating mechanisms of resistance to RAF inhibitors. These studies form the basis for new combination therapy strategies for mutant BRAF melanomas. Additionally, we are utilizing the next-generation of RAF inhibitor in pre-clinical models for first-line treatment, as well as second-line treatment of resistant tumors.
Other projects in the laboratory include: the analysis of the signaling pathways downstream of mutant NRAS, which is altered in 15% of melanomas that do not have BRAF mutations; determining the response of melanomas to cyclin-dependent kinase inhibitors; and response of metastatic uveal melanoma to targeted therapeutic agents.
These studies in the laboratory are funded by grants from the National Cancer Institute, Melanoma Research Alliance, Melanoma Research Foundation, and the Adelson Medical Research Foundation.
The laboratory collaborates with clinicians in the Melanoma Center of Excellence at Jefferson and with melanoma researchers at the University of Pennsylvania and the Wistar Institute. The strength of these interactions is illustrated by our joint publications. Through our research, we aim to promote the bi-directional flow of new discoveries between the laboratory and the bedside.