FY25 DNA-PK Inhibition in Neuroblastoma

DNA-PK inhibition to Enhance Chemotherapeutic Efficiency in MYCN-Amplified Neuroblastomas Project Summary/Abstract. NB is the most common extracranial solid tumor in children and accounts for ~15% of all pediatric cancer deaths (1). Children with high-risk disease have poor outcomes despite chemotherapy, radiation, surgery, and immunotherapy, highlighting the need to identify new strategies for treatment or to augment current treatment strategies. PRKDC gene encodes DNA-PK, a key regulator of repair responses to double-strand DNA breakages induced by radiation therapy (3). We have demonstrated that high PRKDC expression is associated with poor overall survival, and PRKDC expression is enhanced within MYCN amplified neuroblastomas. The mechanism of primary and acquired chemotherapy resistance in NBs is poorly understood, and the contribution of DNA-PK expression and activity in overcoming chemotherapeutic resistance is not known. Therefore, this project will examine DNA-PK expression and MYCN-amplification as the mechanism of chemotherapeutic resistance in NB tumors and the therapeutic potential of DNA-PK inhibition to overcome this resistance to in MYCN-amplified tumors. The ultimate translational goal of our collaborative and multidisciplinary proposal is to develop an effective, less toxic approach to enhance efficiency of chemotherapy in patients with MYCN-amplification. Therefore, in Aim 1, we will elucidate the role of MYCN- amplification in reprogramming of DNA repair pathways in order to maintain genomic stability and promote survival of cancer cells. In Aim 2, we will test the hypothesis that DNA-PK promotes MYCN-amplified cell survival after chemotherapy. Finally, in Aim 3, we will test the effect of DNA-PK inhibition in combination with chemotherapy on cell survival in NB patient- derived xenografts (PDXs) and NB metastasis models.