Brookline, MA, United States
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Zhou J.,Dana-Farber Cancer Institute | Zhou J.,Melanoma Disease Center | Yuen N.K.,University of Hawaii at Manoa | Zhan Q.,Brigham and Women's Hospital | And 5 more authors.
Cancer Immunology, Immunotherapy | Year: 2012

Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families. Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein was utilized to screen cellular responses in stage I-IV patients and healthy controls by ELISPOT. A broad array of CD4 + and CD8 + cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLAA*0201 epitopes were analyzed further for frequency of reactivity. The generation of specific CD4 + and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis support the development of ML-IAP as a disease marker and therapeutic target. © The Author(s) 2011.

Wu X.,Dana-Farber Cancer Institute | Wu X.,Melanoma Disease Center | Zhou J.,Dana-Farber Cancer Institute | Zhou J.,Melanoma Disease Center | And 7 more authors.
Melanoma Research | Year: 2012

Uveal melanoma (UM) has a high propensity to develop hepatic metastases. We sought to define the mechanisms required for preferential liver homing and to understand further the biologic behavior of this disease. The Met tyrosine kinase receptor and its ligand hepatocyte growth factor are expressed in hepatocytes. We therefore considered Met/hepatocyte growth factor signaling as a candidate migration/growth factor for UM cells. We further explored the relationship between c-Met and other growth factor receptors prevalent in the liver and their roles in UM metastatic potential. UM cell lines were evaluated for c-Met, epidermal growth factor receptor (EGFR), and insulin-like growth factor-1R (IGF-1R) expression by immunoblotting, and gene amplification by comparative genomic hybridization and fluorescence in-situ hybridization. High c-Met, phosphorylated c-Met, and EGFR expression were noted in two of nine cell lines, independent of IGF-1R levels. Knockdown of c-Met decreased proliferation of high c-Met-expressing UM cells but did not induce apoptosis. Selective inhibitors of EGFR and IGF-1R decreased proliferation and induced apoptosis in UM cells regardless of the expression levels of c-Met, EGFR, and IGF-1R. Although c-Met, EGFR, and IGF-1R play proliferative roles, EGFR and IGF-1R are also critical for UM cell survival. High c-Met/EGFR-expressing cell lines possessed the greatest migration potential. c-Met knockdown and selective inhibitors of c-Met, EGFR, and IGF-1R revealed independent contribution of these receptors to migration. UM can be categorized by levels of c-Met and EGFR expression which are associated with migratory/invasiveness responses to soluble factors present at high levels in the liver. This provides biologic relevance for UM clinical behavior with potential therapeutic implications. Melanoma Res 22:123-132 © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Wu X.,Dana-Farber Cancer Institute | Wu X.,Melanoma Disease Center | Marmarelis M.E.,Harvard University | Hodi F.S.,Dana-Farber Cancer Institute | Hodi F.S.,Melanoma Disease Center
PLoS ONE | Year: 2013

Heat shock protein 90 (HSP90) is involved in the regulation of diverse biological processes such as cell signaling, proliferation and survival, and has been recently recognized as a potential target for cancer therapy. Ganetespib is a potent ATP competitive inhibitor of HSP90. Ganetespib downregulated the expression of multiple signal transducing molecules including EGFR, IGF-1R, c-Met, Akt, B-RAF and C-RAF, resulting in pronounced decrease in phosphorylation of Akt and Erk1/2 in a panel of five cutaneous melanoma cell lines including those harboring B-RAF and N-RAS mutations. Ganetespib exhibited potent antiproliferative activity on all five of these cell lines, with IC50 values between 37.5 and 84 nM. Importantly, Ganetespib is active on B-RAF mutated melanoma cells that have acquired resistance to B-RAF inhibition. Ganetespib induced apoptosis and cell cycle arrest at G1 and/or G2/M phase. Ganetespib induced cell cycle arrest was accompanied by altered expression of cyclin-dependent kinase inhibitor (CDKI) p21Cip1 and p27Kip1, cyclins B1, D1 and E, and/or cyclin-dependent kinases 1, 2 and 4. HSP90 is functionally important for melanoma cells and HSP90 inhibitors such as ganetespib could potentially be effective therapeutics for melanoma with various genetic mutations and acquired resistance to B-RAF inhibition. © 2013 Wu et al.

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