Clinical evidence has convincingly shown that the BRAF inhibitors (BRAFi) like vemurafenib induce objective tumor regression in >50% of patients with metastatic melanoma that bear the V600E BRAF mutation. However, the tumor regressions are infrequently complete and disease progression occurs at a median of 6-7 months of treatment. Multiple mechanism(s) have been found to support the intrinsic and acquired resistance of melanoma cells to BRAFi and represent major limitations to the use of BRAFi as a single agent in patients with advanced melanoma. Therefore, it is now critical to define combinatorial strategies to eradicate BRAFi sensitive and resistant melanoma cells. In this proposal we will test the hypothesis that BRAFi (vemurafenib) enhances the therapeutic efficacy of IFN?-2b in patients with metastatic melanoma. This hypothesis stems from our novel findings that BRAFi: 1) enhances the sensitivity of melanoma cells to IFN-?-mediated anti-proliferative and proapoptotic activity;2) increases T cell-mediated immune responses to melanoma cells by upregulating tumor antigen presentation and downregulating the expression of inhibitory receptor ligand by melanoma cells and;3) prolongs the survival of melanoma bearing mice. These findings reflect an increased IFN?-2b sensitivity of melanoma cells harboring BRAF mutations upon treatment with BRAFi. To assess the clinical significance of our experimental data, the proposed Specific Aims will test the following hypotheses: 1) The administration of BRAFi and IFN?-2b to patients with metastatic melanoma is safe, non toxic and immunogenic;2) The administration of BRAFi enhances the antiproliferative and proapoptotic activity of the of IFN?-2b as well as its ability to upregulate the expression of HLA class I APM component expression by melanoma cells and;3) The administration of BRAFi and IFN?-2b increases tumor antigen (TA)-specific T cell expansion and function in the tumor microenvironment. The information derived from the outlined studies will contribute to determine the therapeutic relevance of the BRAFi/IFN?-2b combination and the molecular mechanisms underlying its therapeutic effects.

Public Health Relevance

This proposal will test the safety and efficacy of a novel combinatorial therapy with high dose Interferon and Braf inhibitor (vemurafenib). This project may prove critical for the design of potent targeted combinatorial strategies including Braf inhibitor and high dose interferon for patients with melanoma in the therapeutic or adjuvant setting.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA121973-06
Application #
8554637
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Project Start
2006-07-01
Project End
2018-06-30
Budget Start
2013-09-17
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$288,007
Indirect Cost
$98,660
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Retseck, Janet; VanderWeele, Robert; Lin, Hui-Min et al. (2016) Phenotypic and functional testing of circulating regulatory T cells in advanced melanoma patients treated with neoadjuvant ipilimumab. J Immunother Cancer 4:38
Scharping, Nicole E; Menk, Ashley V; Moreci, Rebecca S et al. (2016) The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. Immunity 45:374-88
Villalona-Calero, Miguel A; Duan, Wenrui; Zhao, Weiqiang et al. (2016) Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair. J Natl Cancer Inst 108:
Bengsch, Bertram; Johnson, Andy L; Kurachi, Makoto et al. (2016) Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 45:358-73
Sottile, Rosa; Pangigadde, Pradeepa N; Tan, Thomas et al. (2016) HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors. Eur J Immunol 46:409-19
Fan, Yiping; Lee, Seungjae; Wu, Gang et al. (2016) Telomerase Expression by Aberrant Methylation of the TERT Promoter in Melanoma Arising in Giant Congenital Nevi. J Invest Dermatol 136:339-42
Davar, Diwakar; Kirkwood, John M (2016) Adjuvant Therapy of Melanoma. Cancer Treat Res 167:181-208
Butterfield, Lisa H (2016) Lessons learned from cancer vaccine trials and target antigen choice. Cancer Immunol Immunother 65:805-12
Zarour, Hassane M (2016) Reversing T-cell Dysfunction and Exhaustion in Cancer. Clin Cancer Res 22:1856-64
Blackler, Ryan J; Evans, Dylan W; Smith, David F et al. (2016) Single-chain antibody-fragment M6P-1 possesses a mannose 6-phosphate monosaccharide-specific binding pocket that distinguishes N-glycan phosphorylation in a branch-specific manner†. Glycobiology 26:181-92

Showing the most recent 10 out of 162 publications