BRAF inhibitor therapy has demonstrated an improvement in survival and has gained FDA approval less than ten years from the first reporting of the BRAFV600E mutation in approximately half of melanomas. This record drug development time attests to the high relevance of this new mode of therapy. However, the initial success is limited by the frequent development of acquired resistance to BRAF inhibitors. In this resubmission we propose an integrated project program grant (PPG) with four projects centered on the understanding of how melanomas become resistant to BRAF inhibitors and how combinatorial strategies can be designed to prevent or treat resistance. We have incorporated the critiques and concerns from the initial review and we provide a markedly improved application with the following projects and cores: Project 1 (Lo) proposes a comprehensive study of acquired resistance pathways as targets for combinatorial treatments using integrated genomic platforms coupled with functional experiments. Project 2 (Graeber) uses mass spectrometry-based phosphoprofiling and protein interaction profiling techniques to characterize the signaling events driving resistance from a systems perspective. Project 3 (Tseng) proposes the use of a microfluidic diagnostics toolbox for quantification of multiple signaling and genomic events, optimized for minimally invasive techniques amenable to repeated sampling, to study the process of acquired resistance to BRAF inhibitors. Project 4 (Ribas) tests the combination of BRAF inhibitor therapy and immunotherapy to prevent resistance to single agent BRAF inhibitors in animal models and in the clinic. The Administrative Core A will provide overall support for the activities of the PPG, including comprehensive biostatistics and bioinformatics support. The Biospecimen and Pathology Core B serves as a repository of in-house generated and oncogenically characterized melanoma cell lines and will process and provide new biopsies from patients treated with BRAF inhibitors. Program integration is achieved through the common (but non-overlapping) scientific goals of addressing resistance to BRAF inhibitors by a group of highly collaborative investigators.
The main relevance of the program is based on its translational focus to address a major scientific and clinical problem, the development of acquired resistance to BRAF inhibitors after an initial response. Program integration is achieved through the common (but non-overlapping) scientific goals of addressing resistance to BRAF inhibitors by a group of highly collaborative investigators.
|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|
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