Research And Grants

Targeting Histone Lysine Demethylases to Treat Diffuse Intrinsic Pontine Glioma

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are devastating childhood brain tumors that occur in the central portions of the brain. Traditional chemotherapies do not work on them, and because of their location they cannot be removed by surgery. Radiation therapy slows tumor growth, but progression is inevitable. The failure of traditional chemotherapies to treat DIPG underscores the need for unconventional therapies to treat DMG/DIPG. DMG/DIPG resistance to treatment is due to a genetic mutation in the tumor cells, called H3K27M. This mutation can cause a global loss of a methyl group on a protein called histone, which provides structural support for a chromosome to promote cell growth and survival. The loss of methyl groups can be made even worse by other enzymes, KDM6A and KDM6B, which remove methyl groups from histone. We hypothesize that blocking the activity of the KDM6A/B enzymes will restore the methyl group on histone and therefore inhibit DIPG growth. To inhibit the activity of these enzymes, we have engineered an adeno-associated virus (AAV) system to silence KDM6A/B. AAV viral vector systems have been used to treat a variety of human diseases. Our initial in vivo study has shown more than 80% overall survival in the AAV-treated mice; therefore, an AAV system may hold great promise for DMG/DIPG patients by allowing for safe and effective treatment. In the proposed study, we will examine the effects of KDM6A/B silencing on the growth of different patient-derived DIPG/DMG tumor cells and we will optimize the AAV targeting platform to improve outcome metrics for survival and efficacy. Our targeting platform will allow us to bypass drug accessibility issues in the brainstem and to precisely target one or more specific tumor-promoting genes. This information will allow clinicians to design novel treatment strategies for DMG/DIPG in future clinical trials and will improve therapy efficacy and patient survival.