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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114337-08
Application #
8327769
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Thurin, Magdalena
Project Start
2005-04-15
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$351,145
Indirect Cost
$141,156
Name
California Pacific Medical Center Research Institute
Department
Type
DUNS #
071882724
City
San Francisco
State
CA
Country
United States
Zip Code
94107
Bezrookove, Vladimir; De Semir, David; Nosrati, Mehdi et al. (2014) Prognostic impact of PHIP copy number in melanoma: linkage to ulceration. J Invest Dermatol 134:783-90
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
Dar, Altaf A; Majid, Shahana; de Semir, David et al. (2011) miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein. J Biol Chem 286:16606-14
DeLisser, Horace; Liu, Yong; Desprez, Pierre-Yves et al. (2010) Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression. Proc Natl Acad Sci U S A 107:18616-21
Dar, Altaf A; Majid, Shahana; Nosrati, Mehdi et al. (2010) Functional modulation of IGF-binding protein-3 expression in melanoma. J Invest Dermatol 130:2071-9
Kashani-Sabet, Mohammed; Venna, Suraj; Nosrati, Mehdi et al. (2009) A multimarker prognostic assay for primary cutaneous melanoma. Clin Cancer Res 15:6987-92
Kashani-Sabet, Mohammed; Rangel, Javier; Torabian, Sima et al. (2009) A multi-marker assay to distinguish malignant melanomas from benign nevi. Proc Natl Acad Sci U S A 106:6268-72

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