The focus of our laboratory research is on metabolic signaling in melanoma. We are interested in understanding how rewired metabolism in cancer cells is coordinated with other hallmarks of cancer to influence cancer initiation, promotion and progression. Approximately half of all melanomas harbor an activating mutation in BRAF (BRAFV600E) that drives cancer growth due to the constitutive activation of the downstream MEK/ERK pathway. The “addiction” of melanomas harboring this BRAF mutation has stimulated the development of BRAF inhibitors (BRAFi), such as Vemurafenib and Dabrafenib. These BRAFi have shown great clinical benefits in malignant melanoma with BRAFV600E mutations in the initial phase of treatment. However, the vast majority of the responsive melanoma patients treated with BRAF inhibitors develop resistance during the course of treatment and relapsed. In addition to the BRAF-targeted therapy, another recent major groundbreaking approach in melanoma treatment is to target the immune checkpoints that exploit melanoma’s intrinsically high immunogenicity. Biological drugs that target CTLA-4, PD-1 or PD-L1 have shown significant clinical benefits in melanoma patients with a high degree of durable responses, but only in a subset of patients. Therefore, improving the response rates of immunotherapies and overcoming BRAFi resistance represent two of the greatest challenges facing this field. The overarching goal of our research is to address this by gaining a better understanding of metabolic programming in melanoma and to translate these basic research findings into better strategies for melanoma prevention, diagnosis and treatment. Preclinical work from his laboratory on AMPK and phenformin have led to a Phase I clinical trial evaluating phenformin with the dabrafenib BRAF inhibitor and trametinib MEK inhibitor combination in patients with BRAF mutant melanoma.
In particular, we currently focus on the following areas of research:
1) BRAF-dependent metabolic wiring and rewiring;
2) Metabolic heterogeneity in cancer;
3) Metabolic regulation of tumor immunity;
4) Roles of AMPK at the interface of metabolism and Cancer;
5) Reviving Phenformin for Cancer Therapy.