The aim of all projects in this application is to identify the mechanisms of resistance to BRAF inhibitors so that effective new therapies can be developed. The Biosample and Pathology Core (Core B) will provide access to melanoma biosamples (tissues and biofluids), cell lines and critical pathology services;together, these are essential to the success of the proposed projects. The Core will accomplish this by:
Specific Aim 1. Provide well-characterized melanoma tissues, cell lines and short-term cultures from patients treated with BRAF inhibitors and prospectively develop additional cell lines from patient samples. The Core will be the repository for existing and prospectively collected melanoma tissues and cell lines, including those from patients treated with BRAF inhibitors. The BPC core also will deposit all isogenic pairs of parental BRAF inhibitor-sensitive and -resistant sublines derived in the laboratory, a proven model system to discover and mechanistically dissect acquired resistance pathways. All cell lines will be available to all four Projects and Core C for characterization and analyses.
Specific Aim 2 : Centralized performance of specialized pathology services. The Core prospectively will procure biosamples (tissues and biofluids) and maintain a web-based melanoma biorepository database (Daedalus Software) to permit live entry of samples at unlimited locations with customized clinical annotation. Standardized procedures ensure appropriate sample tracking/distribution, regulatory compliance (coordinated with Core A), and quality control. The Core will offer histology, immunohistochemistry, immunofluorescence, high throughput digital slide scanning and automated digital analysis. Testing will be developed for research and CLIA-certified settings. The Core will provide expert pathologic evaluation of therapeutic response during treatment and tissue/FNA quality standardization (e.g., percentage tumor content) for high throughput sequencing (Project 1) and microfluidic assisted diagnostics (Project 3).
Specific Aim 3 : Develop criteria to evaluate treatment response in cytology samples, including fine needle aspirations (FNAs). To foster Project 3 (develop new molecular techniques to evaluate molecular signaling and resistance signatures from small numbers of cells), we will determine the complementary histopathologic features of response (or lack thereof) on small samples so as to develop objective pathologic criteria of response.

Public Health Relevance

All proposed projects require human melanoma biosamples and pathology services. This Core has banked tissues/cell lines from patients treated with BfRAF inhibitors and will continue to collect, track, prioritize and provide biosamples following national standards;pathology services (histology, immunohistochemistry, immunofluorescence, digital slide scanning and automated digital analysis) and diagnostic expertise also will be provided. These services would be extremely expensive to set up and run outside ofthe Core setting.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-C)
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University of California Los Angeles
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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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