, 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Shi, Qiong; Liu, Hongliang; Han, Peng et al. (2017) Genetic Variants in WNT2B and BTRC Predict Melanoma Survival. J Invest Dermatol 137:1749-1756
Van Roosbroeck, Katrien; Fanini, Francesca; Setoyama, Tetsuro et al. (2017) Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers. Clin Cancer Res 23:2891-2904
Kim, Dae Won; Haydu, Lauren E; Joon, Aron Y et al. (2017) Clinicopathological features and clinical outcomes associated with TP53 and BRAFNon-V600 mutations in cutaneous melanoma patients. Cancer 123:1372-1381
Fang, Shenying; Vaysse, Amaury; Brossard, Myriam et al. (2017) Melanoma Expression Genes Identified through Genome-Wide Association Study of Breslow Tumor Thickness. J Invest Dermatol 137:253-257
Rodriguez-Aguayo, Cristian; Monroig, Paloma Del C; Redis, Roxana S et al. (2017) Regulation of hnRNPA1 by microRNAs controls the miR-18a-K-RAS axis in chemotherapy-resistant ovarian cancer. Cell Discov 3:17029
Mbofung, Rina M; McKenzie, Jodi A; Malu, Shruti et al. (2017) HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nat Commun 8:451
Reuben, Alexandre; Spencer, Christine N; Prieto, Peter A et al. (2017) Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. NPJ Genom Med 2:
Singh, Tarjinder; Walters, James T R; Johnstone, Mandy et al. (2017) The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat Genet 49:1167-1173
Li, Hong; Wang, Yanru; Liu, Hongliang et al. (2017) Genetic variants of PDGF signaling pathway genes predict cutaneous melanoma survival. Oncotarget 8:74595-74606
Eskiocak, Banu; McMillan, Elizabeth A; Mendiratta, Saurabh et al. (2017) Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma. Cancer Discov 7:832-851

Showing the most recent 10 out of 271 publications