• Share:

 

The Wistar Institute

3601 Spruce Street

Philadelphia, PA 19104

 

Office: 215-898-3971

Research

We are actively studying the molecular mechanisms mediating drug resistance in melanoma. Our team is particularly interested in the role of the RAF/MEK and PI3K/mTOR pathways as therapeutic targets and the mechanisms underlying resistance to inhibitors that block these signaling networks. Our research is currently focused on 2 interrelated projects:

1. Mechanisms of drug resistance in melanoma.

We have developed pre-clinical models that show how melanoma gains resistance to BRAF, MEK, and the combination of both inhibitors. Using these models, we have demonstrated that melanoma cells treated with RAF inhibitors bypass the effects of the drugs by activating alternative signaling pathways, including RTKs, PI3K/mTOR and STAT3.

As melanoma is a highly heterogeneous disease, multiple mechanisms of resistance are likely to arise in patients. We are using an array of biochemical and genetic approaches to identify additional mechanisms of resistance and testing combinations of different inhibitors targeting the resistant pathways. Our goal is to identify the best combination therapies that can overcome resistance to BRAF/MEK inhibitors and could move forward into clinical trials.

2.   Developing molecular approaches to target NRAS mutant melanomas.

NRAS is a poorly characterized RAS family member, and the pathways downstream of NRAS remain inadequately understood. There are very limited treatment options for patients whose tumors have NRAS mutations, which are present in 25% of all melanomas. As targeting RAS directly has thus far not been successful, our aim is to eradicate this type of tumors by blocking downstream RAS effectors. Consequently, we are using genetic and proteomic approaches to identifying NRAS effectors critical for survival of melanoma cells and evaluating the effect of inhibiting NRAS effectors on tumor cell proliferation, viability, and apoptosis. To this end, we are using clinically relevant compounds in a variety of in-vitro and in-vivo melanoma models.