A number of Aurora kinase inhibitors are already in clinica

We identified the immunoglobulin like transcript 2 gene that was significantly down regulated in T cells exposed to the recombinant Vaccinia vectors using a gene microarray strategy. ILT2 is a negative regulatory protein that inhibits T cells responses and decreases in ILT2 were associated KU-0063794 臨床試験 with therapeutic responses in vaccinated patients, suggesting this might be a useful biomarker of clinical response. An attenuated, recombinant herpes simplex type 1 virus encoding GM CSF has been constructed. This vector has demonstrated regression of both injected and uninjected tumors in murine models.<br>br<> Lenalidomide 臨床試験 HSV 1 encoding human GM CSF was constructed and has been named Talimogene Laherparepvec, T VEC was shown to be safe in a Phase I clinical trial and was tested in 50 patients with locally advanced and metastatic melanoma in a Phase II study, This study further demonstrated limited toxicity, induction of anti herpes viral titers in all patients and objective regression of tumors in 28% of the treated patients, including regression of distant, un injected melanoma. Selected patients also had biopsy specimens taken after vaccin ation which revealed the induction of a MART 1 specific CD8 T cell response and decreased numbers of CD4 FoxP3 regulatory T cells, CD8 FoxP3 suppressor T cells and MDSCc in injected lesions. Based on these data, a large T VEC has been tested in an international, multi institutional, randomized, controlled phase III clinical trial with results expected in 2013. In summary, understanding of the molecular drivers of melanoma provides opportunities to target the disease in a rational manner that may ultimately reduce the mor tality from the disease.<br>br<> Different signaling pathways have been identified in melanoma with buy LY294002 genomic analysis of primary melanoma giving an insight into the molecular drivers of the disease at an early stage in disease pro gression and include mutations in a variety of genes in cluding well established BRAF, NRAS, KIT, MAPK kinases, and novel genes such RAC1. These genomic changes frequently involve classic oncogenic pathways including the PI3K AKT mTOR, RAS RAF MEK ERK and the CyclinD1 CDK4 pRB pathways. Mutations in genes that activate these pathways provide opportunities to therapeutically target the disease. Mutations in BRAF in about 50% of melanomas can be inhibited by drugs that target the RAS RAF MEK ERK pathway including vemurafenib, dabrafenib, and trametinib.<br>br<> Similarly, mu tations in NRAS in about 15 18% of melanomas also activate the RAS RAF MEK ERK pathway that can be inhibited by MEK inhibitors such as MEK 162. Other therapeutic opportunities exist in targeting mutations in ERBB4 present in about 10% of melanoma patients that could be inhibited by lapatinib. Upregulated EphB4 re ceptor expression present in about 10% of melanomas could be inhibited by nilotinib, and imatinib, sunitinib; and nilotinib inhibit KIT mutations that occur in about 3 5% of melanomas. BRAF inhibitors have dramatically changed the out come of patients with advanced disease that contain mu tations at the codon V600.