Research and Clinical Interests
Targeting mutant BRAF and integrin signaling in melanoma.
Melanoma arises from epidermal melanocytes, the pigment producing cells in the skin, or their progenitors. Currently, melanoma metastasis is only preventable by early detection and surgical excision of primary tumors; hence, there is an immediate need to understand the mechanisms underlying melanocyte transformation. We utilize molecular and clinical grade inhibitor approaches to alter key signaling pathway in primary human melanocytes and a panel of melanoma cells characterizing different stages of melanoma progression. We test the role of target proteins in 3D skin mimetic in vitro systems and an intradermal in vivo imaging model.
The serine/threonine kinase, B-RAF, is somatically mutated in ~60% of melanomas. Mutant B-RAF hyper-activates signaling, which is required for melanoma growth and invasion. One focus in the laboratory is determining the effectors of mutant B-RAF signaling that elicit malignant traits in melanoma cells. We have shown a role for Bcl-2 family proteins and integrin-mediated adhesion in the survival properties of melanoma cells, and a function for the GTPase, Rnd3, in cell invasion and migration in 3D. Recently, we have identified a stemness factor, FOXD3, which is up-regulated in mutant B-RAF melanoma cells following targeting of the mutant B-RAF signaling pathway. We are currently investigating the role of up-regulated FOXD3 in melanoma. Ultimately, we expect to identify the mechanisms underlying invasive growth of melanomas and, in doing so, identify novel targets for therapeutic intervention.
Clinical trials utilizing RAF inhibitors in late-stage mutant B-RAF melanoma patients are underway. The majority of patients enrolled in a recent RAF inhibitor trials showed dramatic clinical responses. Unfortunately, most of the original responders are now eliciting drug resistance. This acquired/secondary resistance is a major obstacle to the prolonged effects of kinase inhibitor therapies. We are elucidating modes of resistance to RAF inhibitors with the view that identifying novel RAF inhibitor resistance mechanisms will direct new combinatorial trials for melanoma.