Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma.

Malignant astrocytoma includes anaplastic astrocytoma (grade III) and glioblastoma (grade IV). Among them, glioblastoma is the most common primary brain tumor with dismal responses to all therapeutic modalities. We performed a large-scale, genome-wide microRNA (miRNA) (n=756) expression profiling of 26 glioblastoma, 13 anaplastic astrocytoma and 7 normal brain samples with an aim to find deregulated miRNA in malignant astrocytoma. We identified several differentially regulated miRNAs between these groups, which could differentiate glioma grades and normal brain as recognized by PCA. More importantly, we identified a most discriminatory 23-miRNA expression signature, by using PAM, which precisely distinguished glioblastoma from anaplastic astrocytoma with an accuracy of 95%. The differential expression pattern of nine miRNAs was further validated by real-time RT-PCR on an independent set of malignant astrocytomas (n=72) and normal samples (n=7). Inhibition of two glioblastoma-upregulated miRNAs (miR-21 and miR-23a) and exogenous overexpression of two glioblastoma-downregulated miRNAs (miR-218 and miR-219-5p) resulted in reduced soft agar colony formation but showed varying effects on cell proliferation and chemosensitivity. Thus we have identified the miRNA expression signature for malignant astrocytoma, in particular glioblastoma, and showed the miRNA involvement and their importance in astrocytoma development.

Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma.

The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors.