2010 has been called the "Year of Melanoma" by cancer scientists and physicians. In 2011, we witnessed the FDA approval of a BRAF inhibitor (vemurafenib/Zelboraf) and an immunomodulatory agent (ipilimumab/Yervoy) for the treatment of advanced melanoma. Although BRAF inhibitors can induce unprecedented response rates in excess of 50%, most tumor responses are partial (i.e., acute resistance) and most patients who initially respond later suffer disease progression (i.e., acquired resistance). Thus, overcoming BRAF inhibitor resistance promises to significantly advance melanoma patient survivability. We propose achieving this important goal by understanding each and every mechanism of resistance in order to effectively devise combinatorial targeted therapies based on common denominator core pathways. The Lo Laboratory has a proven track record in integrating genomic and functional analyses to uncover acquired resistance mechanisms operative in BRAF inhibitor-treated patients (3-8). These studies have already suggested combinatorial treatment strategies being tested currently in clinical trials (e.g. BRAF inhibitor + MEK inhibitor). We propose in Aim 1 to leverage next-generation sequencing to comprehensively understand the mechanisms of BRAF inhibitor resistance in melanoma.
In Aim 2, we propose experiments to study specific epigenetic pathways that contribute to a form of chromatin-mediated and potentially reversible type of drug resistance.
In Aim 3, we propose a large-scale functional genomic approach utilizing RNAi to understand V600E BRAF co-dependent and synthetic lethal genes. This understanding should shed key insights into mechanisms of primary resistance in patients treated with BRAF inhibitors. With the other leaders of this P01 Program Project Grant, we are building a comprehensive melanoma program to overcome BRAF inhibitor resistance in melanoma. Our forward and reverse translational approaches are founded in existing team work that has already proven productive. The combination of medical and surgical expertise (Drs. Ribas and Lo) and basic science approaches (Drs. Graeber and Tseng) to solve this important biologic and clinical problem promises to make the 2010 melanoma turning point a story for the ages.

Public Health Relevance

Resistance to targeted therapy is the rule rather than the exception. Understanding and overcoming targeted drug resistance is arguably the next cancer research frontier. We are starting to witness mechanisms of acquired BRAF inhibitor resistance in melanoma re-surfacing as ways by which other BRAF mutant human malignancies escape from BRAF inhibition (9). There is thus little doubt that studying melanoma as a prototypic BRAF mutant malignancy would have wide-reaching therapeutic relevance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA168585-02
Application #
8686785
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
$315,423
Indirect Cost
$110,206
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