Mortality from melanoma is rising due to the increase in incidence and lack of effective therapy once the disease has metastasized. One of the most promising new therapies is carboplatin (C), paclitaxel (T) and BAY43-9006 (B), which revealed very high response rates with unusually long mean time to disease progression in a Phase l/ll trial in metastatic melanoma. ECOG is opening a randomized trial comparing CT to CTB, called E2603. The precise mechanism of BAY 43-9006 is unknown, and response to CTB appears not to be associated with B-RAF activating mutations. We hypothesize that (a) mechanisms other than B-RAF inhibition are involved in the activity of this combination of drugs and (b) CTB will benefit only a subset of melanoma patients. We strive to find markers that predict response in the individual patient in order to ultimately treat only those patients that are likely to respond. We will screen selected markers for association with response to therapy, and perform comprehensive analysis on the best predictive markers. We will use a novel, objective, automated quantitative method of tissue microarray analysis (AQUA) to evaluate expression of proteins from three groups that are known to be induced by these drugs; the MARK pathway, apoptotic pathways and pro-angiogenic proteins. We will start with rigorous validation of antibodies to a subset of these proteins, followed by initial evaluation on tumors from 50 patients treated with CTB in the Phase l/ll study. Markers with differences in expression between responders and non-responders will be further evaluated on 300 archival melanoma specimens and 300 benign nevi to assess prevalence of markers expression in metastatic melanomas. Concurrently, specimens from patients enrolled in E2603 will be prospectively collected. Using AQUA on tissue microarrays, we will study differences in marker expression between responders and non-responders on both treatment arms, with the goal of developing an assay to specifically predict response to CTB. We will assess individual markers as well as panels of markers. ? ?
| Wilson, Melissa A; Zhao, Fengmin; Khare, Sanika et al. (2016) Copy Number Changes Are Associated with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in Melanoma. Clin Cancer Res 22:374-82 |
| Wilson, Melissa A; Zhao, Fengmin; Letrero, Richard et al. (2014) Correlation of somatic mutations and clinical outcome in melanoma patients treated with Carboplatin, Paclitaxel, and sorafenib. Clin Cancer Res 20:3328-37 |
| Jilaveanu, Lucia B; Zhao, Fengmin; Zito, Christopher R et al. (2013) Expression of drug targets in patients treated with sorafenib, carboplatin and paclitaxel. PLoS One 8:e69748 |
| Jilaveanu, Lucia B; Zito, Christopher R; Aziz, Saadia A et al. (2011) In vitro studies of dasatinib, its targets and predictors of sensitivity. Pigment Cell Melanoma Res 24:386-9 |
| Kluger, Harriet M; Dudek, Arkadiuz Z; McCann, Carrie et al. (2011) A phase 2 trial of dasatinib in advanced melanoma. Cancer 117:2202-8 |
| Mehnert, Janice M; McCarthy, Mary M; Jilaveanu, Lucia et al. (2010) Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays. Hum Pathol 41:375-84 |
| Aziz, Saadia A; Jilaveanu, Lucia B; Zito, Christopher et al. (2010) Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. Clin Cancer Res 16:6029-39 |
| Jilaveanu, Lucia B; Aziz, Saadia A; Kluger, Harriet M (2009) Chemotherapy and biologic therapies for melanoma: do they work? Clin Dermatol 27:614-25 |
| Aziz, Saadia A; Davies, Michael; Pick, Elah et al. (2009) Phosphatidylinositol-3-kinase as a therapeutic target in melanoma. Clin Cancer Res 15:3029-36 |
| Jilaveanu, Lucia B; Zito, Christopher R; Aziz, Saadia A et al. (2009) C-Raf is associated with disease progression and cell proliferation in a subset of melanomas. Clin Cancer Res 15:5704-13 |
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