, Melanoma is a common and deadly tumor that frequenfiy metastasizes to the central nervous system (CNS), resulting in a median survival durafion of 3.7 month and refractoriness to conventional therapy. A key transcripfionalfactor, signal transducer and activator of transcription (STAT)-3, drives the components of melanoma and is over expressed in 80% of melanoma CNS metastases,. Phosphorylated STAT-3 propagates turhorigenesis by enhancing proliferation, angiogenesis, invasion, metastasis, and mmunosuppression. We developed WP1066, a potent orally administered inhibitor of STAT-3 that displays marked efficacy against established intracerebral melanoma in vivo. The mechanism of WP1066's activity is a combinafion of direct melanoma cytotoxicity and immune cytotoxic clearance. In this proposed study, we will further clarify the mechanisms of activity and targets of WP1066 using murine melanoma models of metastasis to identify biomarkers and potenfial selecfioh criteria for a Phase l/ll cliriical trial. This study will focus on whether over expression of phosphorylated STATS in the parenchymal tumors of patients with stage IV melanoma is predictive of CNS metastasis and whether this over expression is an independent predictor of survival. We have demonstrated that a significant mechanism of WP1066's activity is enhancement of CD8+ T-cell effector resporises and inhibifion of regulatory T cells: Immunotherapy with both interferon-alpha and interieukin-2 is used for melanoma, but the response rates remain low. We will further determine vyhether WP1066 Can markedly improve these immunotherapy modalities in in vivo murine model systems. These studies will lay the groundwork for a potenfial clinical trial of WP1066 as an immunomodulator. These following specific aims are the basis for conducting these studies: 1) Evaluate mechanisms of activity of WP1066 and identify biological markers for a clinical trial of WP1066;2) Evaluate the natural history of p-STAT-3 expression in patients with melanoma and determine whether WP1066 can impact these processes in in vivo murine models to clarify clinical trial design;3) Establish whether reversing immune suppression with WP1066 is synergisfic with other immunotherapies for melanoma. These translational studies will bring to the forefront a novel therapeufic that has real potential to improve the survival of patients with melanoma havirig CNS metastatic disease, a major unmet clinical need.

Public Health Relevance

Stage IV melanoma patients with CNS metastasis have few therapeutic options and are a greatly underserved population. Our intenfion is to implement clinical trials with WP1066 in melanoma patients with established CNS metastasis, determine if we can predict which stage IV melanoma pafients are at risk for CNS metastasis, arid to develop STAT-3 inhibitors as potent immune modulators to be potenfially used in combination with other approved immune therapeutics that have limited clinical efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA093459-09
Application #
8541566
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$277,339
Indirect Cost
$78,464
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing et al. (2015) Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. Clin Cancer Res 21:611-21
Fang, Shenying; Wang, Yuling; Chun, Yun Shin et al. (2015) The relationship between blood IL-12p40 level and melanoma progression. Int J Cancer 136:1874-80
Siroy, Alan E; Boland, Genevieve M; Milton, DenĂ¡i R et al. (2015) Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma. J Invest Dermatol 135:508-15
Chattopadhyay, Chandrani; Grimm, Elizabeth A; Woodman, Scott E (2014) Simultaneous inhibition of the HGF/MET and Erk1/2 pathways affect uveal melanoma cell growth and migration. PLoS One 9:e83957
Sim, Geok Choo; Chacon, Jessica; Haymaker, Cara et al. (2014) Tumor-infiltrating lymphocyte therapy for melanoma: rationale and issues for further clinical development. BioDrugs 28:421-37
Rees, Elliott; Walters, James T R; Georgieva, Lyudmila et al. (2014) Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry 204:108-14
Lopez-Rivera, Esther; Jayaraman, Padmini; Parikh, Falguni et al. (2014) Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2. Cancer Res 74:1067-78
Boraska, V; Franklin, C S; Floyd, J A B et al. (2014) A genome-wide association study of anorexia nervosa. Mol Psychiatry 19:1085-94
Singh, Manisha; Khong, Hiep; Dai, Zhimin et al. (2014) Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193:4722-31
Wang, Yun; Hu, Shougang; Gabisi Jr, Abdul M et al. (2014) Developing an irreversible inhibitor of human DDAH-1, an enzyme upregulated in melanoma. ChemMedChem 9:792-7

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