2010 has been called the Year of Melanoma by cancer scientists and physicians. In 2011, we witnessed the FDA approval of a BRAF inhibitor (vemurafenib/Zelboraf) and an immunomodulatory agent (ipilimumab/Yervoy) for the treatment of advanced melanoma. Although BRAF inhibitors can induce unprecedented response rates in excess of 50%, most tumor responses are partial (i.e., acute resistance) and most patients who initially respond later suffer disease progression (i.e., acquired resistance). Thus, overcoming BRAF inhibitor resistance promises to significantly advance melanoma patient survivability. We propose achieving this important goal by understanding each and every mechanism of resistance in order to effectively devise combinatorial targeted therapies based on common denominator core pathways. The Lo Laboratory has a proven track record in integrating genomic and functional analyses to uncover acquired resistance mechanisms operative in BRAF inhibitor-treated patients (3-8). These studies have already suggested combinatorial treatment strategies being tested currently in clinical trials (e.g. BRAF inhibitor + MEK inhibitor). We propose in Aim 1 to leverage next-generation sequencing to comprehensively understand the mechanisms of BRAF inhibitor resistance in melanoma.
In Aim 2, we propose experiments to study specific epigenetic pathways that contribute to a form of chromatin-mediated and potentially reversible type of drug resistance.
In Aim 3, we propose a large-scale functional genomic approach utilizing RNAi to understand V600E BRAF co-dependent and synthetic lethal genes. This understanding should shed key insights into mechanisms of primary resistance in patients treated with BRAF inhibitors. With the other leaders of this P01 Program Project Grant, we are building a comprehensive melanoma program to overcome BRAF inhibitor resistance in melanoma. Our forward and reverse translational approaches are founded in existing team work that has already proven productive. The combination of medical and surgical expertise (Drs. Ribas and Lo) and basic science approaches (Drs. Graeber and Tseng) to solve this important biologic and clinical problem promises to make the 2010 melanoma turning point a story for the ages.
Resistance to targeted therapy is the rule rather than the exception. Understanding and overcoming targeted drug resistance is arguably the next cancer research frontier. We are starting to witness mechanisms of acquired BRAF inhibitor resistance in melanoma re-surfacing as ways by which other BRAF mutant human malignancies escape from BRAF inhibition (9). There is thus little doubt that studying melanoma as a prototypic BRAF mutant malignancy would have wide-reaching therapeutic relevance.
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