Epigenetic control of cell state in retinoid resistant neuroblastoma
Mentor Name: A. Look
Neuroblastoma is the most frequent, non-brain solid tumor in childhood. Patients with high-risk disease have poor outcomes despite intensified treatment--including high-dose chemotherapy, stem cell rescue, immunotherapy, and maintenance treatment with retinoic acid. Retinoic acid, which is orally available and generally well tolerated, is given to patients during maintenance therapy and induces neuronal differentiation and growth arrest; however, these effects are reversible when retinoic acid is withdrawn. In previous studies, we performed a drug screen with a library of more than 450 small molecules targeting epigenetic modifiers and treated retinoic acid-sensitive neuroblastoma cells with either each compound in isolation or in combination with retinoic acid to identify a small molecule drug that enhances the efficacy of retinoic acid. We found that PF-9363 inhibits cell growth synergistically with retinoic acid and promotes irreversible differentiation of neuroblastoma cells that persists beyond drug removal. Thus, this project will investigate if the combination of PF-9363 and retinoic acid promotes differentiation and prohibits cell growth in neuroblastoma cell lines that are considered resistant to retinoic acid, serving as an improved method to treat children with high-risk neuroblastoma.
