Recent cDN A microarray studies performed in our laboratory have indicated the presence of two dominant subtypes of metastatic melanoma, with potentially different clinical outcomes. cDNA microarray analyses of moles, primary and metastatic melanomas have identified a large number of genes whose expression level can be used to distinguish between the known landmarks in melanoma progression, including genes operating in the NF-kappaB and WNT-2 signaling pathways. In this application, we propose to extend these observations:
Aim 1 : To validate the prognostic significance of the molecular subtypes of metastatic melanoma identified by gene expression profiling in a large cohort of melanoma patients. We will confirm the prognostic impact of gene expression signatures using cDNA microarray analysis on a larger, prospectively identified cohort of metastatic melanoma patients.
Aim 2 : To use systemic, plasmid-based delivery of siRNAs, ribozymes, and cDNAs to characterize the functional roles of four genes identified from our array studies on the metastatic progression of melanoma in mice. We will characterize the functional importance of four genes in the NF-kappaB and WNT-2 signaling pathways on the metastatic progression of melanoma. We will use siRNAs and ribozymes targeting NCOA3, PHIP, and WNT2, and the WIF1 cDNA to validate the importance of each of these genes in the metastatic progression of melanoma.
Aim 3 : To examine expression levels of two candidate melanoma progression genes in a large tissue bank of human melanomas, and to correlate the expression of these genes with melanoma outcome. We will assess whether the protein products of NCOA3 and WNT2 provide new molecular markers to identify human melanoma patients at high risk for metastasis by performing immunohistochemical analysis of routine sections and tissue arrays, using an extensive bank of primary human melanomas. These studies should help validate the role of genes identified by expression profiling in the progression of melanoma.
| de Semir, David; Bezrookove, Vladimir; Nosrati, Mehdi et al. (2018) PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer. Proc Natl Acad Sci U S A 115:E5766-E5775 |
| Kashani-Sabet, Mohammed; Nosrati, Mehdi; Miller 3rd, James R et al. (2017) Prospective Validation of Molecular Prognostic Markers in Cutaneous Melanoma: A Correlative Analysis of E1690. Clin Cancer Res 23:6888-6892 |
| Dar, Altaf A; Majid, Shahana; Bezrookove, Vladimir et al. (2016) BPTF transduces MITF-driven prosurvival signals in melanoma cells. Proc Natl Acad Sci U S A 113:6254-8 |
| Dar, Altaf A; Nosrati, Mehdi; Bezrookove, Vladimir et al. (2015) The role of BPTF in melanoma progression and in response to BRAF-targeted therapy. J Natl Cancer Inst 107: |
| Sun, Vera; Zhou, Wen B; Nosrati, Mehdi et al. (2015) Antitumor activity of miR-1280 in melanoma by regulation of Src. Mol Ther 23:71-8 |
| Bezrookove, Vladimir; De Semir, David; Nosrati, Mehdi et al. (2014) Prognostic impact of PHIP copy number in melanoma: linkage to ulceration. J Invest Dermatol 134:783-790 |
| Sun, V; Zhou, W B; Majid, S et al. (2014) MicroRNA-mediated regulation of melanoma. Br J Dermatol 171:234-41 |
| Dar, Altaf A; Majid, Shahana; Rittsteuer, Claudia et al. (2013) The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression. J Natl Cancer Inst 105:433-42 |
| Kashani-Sabet, Mohammed; Sagebiel, Richard W; Joensuu, Heikki et al. (2013) A patient-centered methodology that improves the accuracy of prognostic predictions in cancer. PLoS One 8:e56435 |
| De Semir, David; Nosrati, Mehdi; Bezrookove, Vladimir et al. (2012) Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Proc Natl Acad Sci U S A 109:7067-72 |
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