Research Abstract
My clinical and laboratory efforts center on the development of novel treatments for adult and pediatric brain tumors, with a focus on improving radiation therapy for these diseases. In studying genetic abnormalities of brain tumors and pediatric malignancies I aim to translate laboratory discoveries to the clinical treatment of cancer, hoping to help shape targeted therapies for adult and pediatric malignancies. Most recently we studied aberrant chromatin remodeling and activation of the phosphatidylinositol 3-kinase (PI3K) pathway as important mediators of pediatric high-grade glioma pathogenesis. We demonstrated that treatment with a novel, first-in-class dual inhibitor of histone deacetylases (HDACs) and PI3K (CUDC-907), in combination with radiotherapy evoked a potent cytotoxic response in pediatric high-grade gliomas and we identified a novel mechanism of action involving modulation of the DNA damage response by inhibiting radiation-induced DNA repair pathways, including homologous recombination and non-homologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreasing NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response, and exogenous expression of NFκB/FOXM1 rescued CUDC-907-induced cytotoxicity. Together, these findings revealed CUDC-907 as a novel radiosensitizer with potent anti-tumor activity in pediatric high-grade gliomas and have provided the preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy. More globally, this work identified NFκB and FOXM1, and their downstream transcriptional elements, as critical targets for new treatments for pediatric high-grade gliomas. This work has resulted in a multi-institutional clinical trial, testing dual histone deacetylases and PI3K inhibition for pediatric gliomas. My passion for patient care and scientific discovery are reflected in my election to Best Doctors in America soon after completing residency and every year since, along with my productive laboratory, continuously funded since completing training, including Program Project, SPORE, and R01 funding.
