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.
|Atefi, Mohammad; Avramis, Earl; Lassen, Amanda et al. (2014) Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res 20:3446-57|
|Mok, Stephen; Koya, Richard C; Tsui, Christopher et al. (2014) Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res 74:153-61|
|Zimman, Alejandro; Titz, Bjoern; Komisopoulou, Evangelia et al. (2014) Phosphoproteomic analysis of platelets activated by pro-thrombotic oxidized phospholipids and thrombin. PLoS One 9:e84488|
|Lin, Millicent; Chen, Jie-Fu; Lu, Yi-Tsung et al. (2014) Nanostructure embedded microchips for detection, isolation, and characterization of circulating tumor cells. Acc Chem Res 47:2941-50|
|Shi, Hubing; Hong, Aayoung; Kong, Xiangju et al. (2014) A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov 4:69-79|
|Thai, Minh; Graham, Nicholas A; Braas, Daniel et al. (2014) Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication. Cell Metab 19:694-701|
|Senese, S; Lo, Y C; Huang, D et al. (2014) Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development. Cell Death Dis 5:e1462|
|Graham, Nicholas A; Graeber, Thomas G (2014) Complexity of metastasis-associated SDF-1 ligand signaling in breast cancer stem cells. Proc Natl Acad Sci U S A 111:7503-4|
|Shi, Hubing; Hugo, Willy; Kong, Xiangju et al. (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4:80-93|
|Tumeh, Paul C; Harview, Christina L; Yearley, Jennifer H et al. (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-71|
Showing the most recent 10 out of 20 publications