Recent studies in our laboratory have suggested novel approaches to melanoma progression that could serve as the basis for the development of novel biomarkers and therapeutic targets for melanoma. In this proposal, we aim to conduct a biomarker analysis in a prospective cohort, the randomized intergroup trial of adjuvant therapy with high-dose interferon alpha (Eastern Cooperative Group trial E1690).
We aim to validate the role of a multi-marker prognostic assay (with confirmed prognostic impact in two distinct cohorts) in the ECOG cohort. Secondly, we aim to validate the functional role of the fetal Alzheimer (FALZ) gene in the progression of melanoma in murine models. Third, we aim to identify microRNAs (miRNAs) with prognostic significance in a large cohort of melanoma patients. Importantly, these diverse targets were identified by virtue of their differential expression in profiling studies of the same tissue cohort of nevi, primary and metastatic melanomas. Our three specific aims are:
Aim 1 : To perform a molecular prognostic factor analysis on the E1690 cohort. In this aim, we propose correlative studies on tissues from the patient population enrolled in the E1690 trial. We propose to validate the prognostic role of a multi-marker immunohistochemical assay in the E1690 cohort, and to determine its predictive role in assessing benefit to adjuvant therapy with interferon alpha.
Aim 2 : To validate the role of the FALZ gene in melanoma progression in murine models. We will characterize the functional importance of the FALZ gene on the progression of melanoma by examining the role of targeted siRNA-mediated suppression of FALZ in the progression of human melanoma in vivo.
Aim 3 : To develop microRNA profiles in the prognostic assessment of primary melanoma. Recent results obtained in our laboratory have identified differentially expressed miRNAs in the known transitions in melanoma progression. We will examine the prognostic role of ten miRNAs using TaqMan analysis in a large cohort of melanoma patients. If successful, these studies will validate a multi-marker prognostic assay for melanoma, firmly establish a role for FALZ in promoting melanoma metastasis, and identify miRNAs with prognostic significance in melanoma.

Public Health Relevance

This project has direct relevance to public health in that it proposes to validate the role of an assay to predict the prognosis associated with melanoma that could be used to identify which patients should be treated with a treatment called interferon alpha. In addition, it proposes to validate the role of a novel gene (FALZ) as a possible target for melanoma treatment, and to identify novel microRNA markers of melanoma progression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Thurin, Magdalena
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California Pacific Medical Center Research Institute
San Francisco
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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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