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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA168585-01A1
Application #
8475942
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Program Officer
Song, Min-Kyung H
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$1,726,864
Indirect Cost
$599,031
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
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