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.
|Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914|
|Song, Chunying; Piva, Marco; Sun, Lu et al. (2017) Recurrent Tumor Cell-Intrinsic and -Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation. Cancer Discov 7:1248-1265|
|Nowicki, Theodore S; Akiyama, Ryan; Huang, Rong Rong et al. (2017) Infiltration of CD8 T Cells and Expression of PD-1 and PD-L1 in Synovial Sarcoma. Cancer Immunol Res 5:118-126|
|Shin, Daniel Sanghoon; Zaretsky, Jesse M; Escuin-Ordinas, Helena et al. (2017) Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer Discov 7:188-201|
|Su, Yapeng; Wei, Wei; Robert, Lidia et al. (2017) Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. Proc Natl Acad Sci U S A 114:13679-13684|
|Zaretsky, Jesse M; Garcia-Diaz, Angel; Shin, Daniel S et al. (2016) Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med 375:819-29|
|Hong, Candice Sun; Graham, Nicholas A; Gu, Wen et al. (2016) MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4. Cell Rep 14:1590-1601|
|Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse et al. (2016) PD-1 Blockade Expands Intratumoral Memory T Cells. Cancer Immunol Res 4:194-203|
|Homet Moreno, Blanca; Zaretsky, Jesse M; Garcia-Diaz, Angel et al. (2016) Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells. Cancer Immunol Res 4:845-857|
|Ribas, Antoni; Hu-Lieskovan, Siwen (2016) What does PD-L1 positive or negative mean? J Exp Med 213:2835-2840|
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