DISSECTING THE ROLE OF CDK4 AND CYCLIN D1 IN GLIOMA – THERAPEUTIC IMPLICATIONS
Led by Andrew Koff at Memorial Sloan Kettering Cancer
High-grade glial tumors remain amongst the most intractable forms of cancer, despite impressive advances in imaging and diagnosis. Understanding the molecular networks that govern the formation of these malignancies is crucial to the continued development of new treatments to fight this devastating illness. Elevated growth factor signaling leading
to unrestrained cell division is a hallmark of malignant glioma, representing an unshackling of the controls that regulate the normal growth of glial cells. To bypass the regulatory mechanisms that normally prevent such cell division, incipient tumor cells typically elevate the expression of cyclin D1 or cdk4, two molecules that are essential and rate-limiting for cell division. Nevertheless, whether this is required for tumorigenesis and the biological pathways that are affected remains unclear. Recently, cdk4 inhibitors have entered the clinical landscape, which makes overcoming this unmet challenge an imperative that will otherwise hinder the translation of these new pharmaceuticals to glioma therapy. Our published data shows the importance of cyclin D1 and cdk4 to gliomagenesis, both in the tumor cells as well as in the maturation of the tumor microenvironment. This proposal will evaluate the respective contribution(s) each makes to the formation of glial brain tumors using a combination of in vivo tumor modeling and pharmacological intervention, along with in vitro studies in cultured glioma cells. We expect this research to not only advance our understanding of glioma formation, but also reveal the promise of cyclin D1-cdk4 as a viable drug target for glioma therapy.
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