Identification of Essential Kinases in Meningioma by RNA-Interference

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Dr. Ian Dunn, MD

Dysregulated kinase activation plays an essential role in the genesis of most, if not all, human cancers. The identification of kinases that drive oncogenic growth represents a highly attractive strategy for selectively targeting malignant cells. For example, the identification of the BCR-ABL kinase in chronic myelogenous leukemia and the spectacular clinical success of its targeting by imatinib show the potential clinical impact of this approach. Despite a few recent successes, we still lack a comprehensive knowledge of the number and identity of kinases whose activity is essential for the transforming events and maintenance of human cancers.

This is particularly true in meningioma. In part, this deficiency exists because we have lacked the tools to study kinase signaling pathways systematically. Dr. Dunn’s project details the application of a novel genetic approach, RNAi-interference (RNAi), to meningioma cell lines to identify functionally relevant cancer-associated genes which are required for meningioma cell survival. RNAi suppresses the expression of genes in a specific manner, permitting the study of the functions of one or many genes. Potential applications of RNAi to the study of human cancer are broadening: experiments involving gene knockouts to determine gene function may now be carried out in the majority of human cell types, and thousands of genes may be studied in a very reasonable period of time. In a systematic fashion, we hope to identify kinases which are essential for the survival of meningioma cell lines. As our RNAi library expands, we hope to extend this approach to the study of the majority of genes in the human genome in order to determine genetic function in these tumors. This strategy is thus immediately translational in that candidate genes emerging from the screen which are essential to the survival of meningioma cell lines immediately become therapeutic targets.

In addition, recent studies have focused on the potential therapeutic applications of RNA interference. For instance, the ability to silence disease-associated genes in a sustained manner with RNA interference is being explored in a host of cancers and infectious diseases. Thus, RNA interference may provide an efficient and powerful method of elucidating the genetic participants in meningioma and may ultimately represent a viable therapeutic option in their treatment.