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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA168585-02
Application #
8686789
Study Section
Special Emphasis Panel (ZCA1-RPRB-C)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$176,406
Indirect Cost
$61,634
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
Escuin-Ordinas, Helena; Li, Shuoran; Xie, Michael W et al. (2016) Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors. Nat Commun 7:12348
Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse et al. (2016) PD-1 Blockade Expands Intratumoral Memory T Cells. Cancer Immunol Res 4:194-203
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 14:1590-601
Robert, Lidia; Ribas, Antoni; Hu-Lieskovan, Siwen (2016) Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2? Semin Immunol 28:73-80
Shin, Daniel Sanghoon; Zaretsky, Jesse M; Escuin-Ordinas, Helena et al. (2016) Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer Discov :
Tavaré, Richard; Escuin-Ordinas, Helena; Mok, Stephen et al. (2016) An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy. Cancer Res 76:73-82
Titz, Bjoern; Lomova, Anastasia; Le, Allison et al. (2016) JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma. Cell Discov 2:16028
Ribas, Antoni; Hu-Lieskovan, Siwen (2016) What does PD-L1 positive or negative mean? J Exp Med 213:2835-2840
Atefi, Mohammad; Titz, Bjoern; Tsoi, Jennifer et al. (2016) CRAF R391W is a melanoma driver oncogene. Sci Rep 6:27454

Showing the most recent 10 out of 51 publications