Glioblastoma is the most common and the most malignant primary brain tumor with a median life expectancy of 15 months despite multimodal therapy. Its aggressive nature is in part due to its ability to escape immune surveillance and to redundant cell signaling that makes it resistant to single-agent targeted therapies. The cyclin D1-CDK4/6- retinoblastoma signaling axis has been implicated in cancer immune evasion and resistance to receptor tyrosine kinase inhibition in multiple cancers. As this axis is deregulated in 80% of glioblastoma, there is ongoing research into whether inhibition of CDK4/6 sensitizes glioblastoma to immunotherapy. This project builds on this work by exploring the role of the epigenetic machinery that is downstream of CDK4/6 signaling on glioblastoma immune evasion, as well as the role of CDK4/6 signaling on resistance to EGFR inhibition. To that end, we will determine whether inhibition of the polycomb repressor complex 2 (PRC2) or of the DNA methyltransferases (DNMTs) triggers tumor cell-intrinsic anti-tumor immunity, and whether PRC2 or DNMT inhibitors synergize with immune checkpoint blockade in novel immunocompetent patient-derived models of glioblastoma. We will also determine whether combination EGFR and CDK4/6 inhibition synergize in a genetically engineered mouse model of glioblastoma driven by EGFRvIII, the most common EGFR mutation in human glioblastoma. We hope that this work will uncover rational combinations of targeted therapies or targeted therapies with immunotherapy that will serve as new therapeutic strategies for patients with glioblastoma.
Glioblastoma is a common and aggressive primary brain tumor that is resistant to most anti-cancer therapies. Epigenetic and cell signaling changes induced by the CDK4/6 signaling axis may mediate resistance to immunotherapy and EGFR inhibition. This work aims to uncover novel combinations of epigenetic modifiers and immunotherapy, as well as combination EGFR and CDK4/6 inhibitors, that may synergize against glioblastoma.
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