Tumors affecting the brain result in more cancer-related deaths than any other type of tumor in children. It is therefore critical to identify new therapies for these deadly diseases. Among pediatric patients, one of the most devastating brain tumor types is diffuse midline gliomas with the H3K27M mutation, which includes the previously named Diffuse Intrinsic Pontine Glioma (DIPG). Our understanding of this deadly disease has recently been advanced by important discoveries, including the finding that almost all of DIPG tumors harbor the histone H3K27M mutation. This mutation results in global hypomethylation of H3K27 residues and is the pathological hallmark for this disease. How the H3K27M mutation is important for tumorigenesis is still being elucidated. At Mayo Clinic, we have shown that H3K27M mutation reprograms gene expression and histone methylation patterns, and is a key driver for these deadly tumors. We hypothesize this mutation creates unique therapeutic vulnerabilities, which can be exploited to develop novel therapies. In an effort to discover potential drug targets for H3K27M tumors, we performed a large scale drug screen which identified aurora kinase inhibitors (AKI) as a potent class of drugs that decreased the proliferation and survival of H3K27M tumor cell lines. Further testing revealed epigenetic changes with AKI treatment including restoring H3K27me3 levels, and decreased H3S10 and H3S28 phosphorylation. Testing of the aurora kinase A inhibitor alisertib in an orthotopic patient derived xenografts showed decreased tumor size, increased survival and on-target drug effects within the tumor. Based on these exciting results, we hypothesize that inhibition of Aurora Kinase is a targeted approach for treating tumors with the H3K27M mutation. In this proposal, we will elucidate how the H3K27M mutation effects mitosis, the mechanism how AKIs modulate the cell cycle and arrest of mitosis and understand the radiosensitizing effects of these drugs. Next we will understand the molecular mechanisms how aurora kinases modulate the epigenetic landscape and gene expression before and after inhibition. Finally, we will perform the necessary preclinical studies in animal models to support translational efforts in the clinic. We have assembled the necessary team required to successfully complete this project: including Jann Sarkaria, a radiation oncologist who specializes in translational animal research for high-grade gliomas, Ted Hinchcliffe, an expert in mitosis from the Hormel/University of MN, Steven Johnsen, an expert who studies epigenetic regulation in cancer, and the PI, David Daniels, a pediatric neurosurgeon and medicinal chemist, who has developed numerous H3K27M cell lines and studies drug delivery to the brainstem. We believe, together, the proposed studies and team, will not only make basic scientific discoveries aimed at understanding the molecular basis of tumorigenesis, but also lay the foundation for effective therapy for this deadly disease.
Diffuse midline gliomas with the H3K27M mutation, which includes the previously named Diffuse Intrinsic Pontine Glioma (DIPG), are the most aggressive primary malignant brain tumors in children with the median survival of this group about one year after diagnosis with no effective therapies available. Recent studies have identified somatic mutation of the H3F3A gene that encodes the histone H3 variant, H3.3, which results in lysine 27 to methionine change (K27M) in the encoded protein H3.3 in most DIPG tumors. The planned studies will not only make basic scientific discoveries aimed at understanding the molecular basis of tumorigenesis, but also lay the foundation for molecularly targeted therapies for this deadly disease.
