Elucidating the Mechanism of GRK2 in Medulloblastoma Cell Growth and Survival
Brain tumors are the most common cause of cancer-related deaths in children under 15. Medulloblastomas (MBs) are the most prevalent malignant brain cancers in children, representing over 14% of related deaths. There are 4 types of MB, 1 of which has a clear cause and treatments in process. The other 3 have unclear origins, result in worse outcomes, display higher drug resistance, and surviving patients suffer significant side effects from their aggressive treatment. A recent study found that an enzyme my lab has studies in the heart, GRK2, may influence the progression and drug resistance of MB. Work in other cancer models has shown it regulates a gene linked to poor MB outcomes. Further, we found that GRK2 interacts with a protein that regulates the tendency of normal cells to become tumor cells. Herein, I will apply my expertise in measuring, inhibiting, and interfering with GRK2 interactions, and my collaborator’s brain tumor expertise, to investigate the relevance of GRK2 in these 3 types of MB. This project will interrogate the subtype-specific prevalence of GRK2 in MB cell lines and patient tissue samples, test whether GRK2 or proteins it interacts with are regulators of drug resistance and poor outcomes, and translate these studies to a preclinical model of tumor progression. My overall goal is to determine whether GRK2 and/or its interacting partners serve as subtype specific regulators of MB that may serve as relevant drug targets to increase tumor cell death and reduce side effects for children afflicted with MB.
We want to understand how a protein in the heart is driving the growth, progression, and therapeutic resistance in childhood brain tumors. If we can understand this enzyme further, we can use it as a therapeutic target to improve the life and wellbeing of children with brain tumors.