The Regents of the University of Michigan C.S. Mott Children's Hospital Archives - Page 2 of 4

2019

Scholar Grant

Erika Newman

Ann Arbor, MI

Title: Targeting Human DNA Ligases in High-Risk Neuroblastoma

Executive Summary:
The childhood cancer neuroblastoma is the most common extracranial tumor in children. Nearly 50% of patients have high-risk disease that is refractory or relapses despite multimodal therapies. MYCN amplification, tumor cell diploidy, older age at presentation, and segmental chromosomal alterations are associated with poor clinical outcomes. Segmental alterations frequently occur in older children with stage IV tumors and are the strongest predictors of relapse, indicating a role in neuroblastoma pathogenicity. Although sequence analysis of recurrent breakpoint regions in neuroblastoma tumors provides evidence that segmental errors are generated by non-homologous end-joining (NHEJ) of DNA double-strand breaks, components of DNA end-joining have not been targeted in neuroblastoma. On this basis, our overarching hypothesis is that high-risk neuroblastoma tumors have inherent cell survival advantage attributable to differential regulation of human DNA ligases that is clinically relevant. Our hypothesis has been formulated based on our strong preliminary findings demonstrating that DNA Ligase III (LIG3), an enzyme with overlapping function in the ultimate steps of cellular replication and repair, is up-regulated in high-risk neuroblastoma. Selective LIG3 inhibition and gene knockdown is cytotoxic to neuroblastoma cells. Significantly, children with neuroblastoma tumors harboring high expression of LIG3 genes have worse survival outcomes than those with low expression. We propose studies that will elucidate the therapeutic utility of targeting LIG3 in neuroblastoma, and screen individual chemical compounds to identify ligase inhibitors that show efficacy as single agents or potentiate DNA damaging agents. We will use ADMET prediction and intuitive medicinal chemistry-guided approaches to perform an in-depth preclinical pharmacology evaluation of novel LIG3 inhibitors to identify a compound to inhibit DNA ligases in neuroblastoma. For efficacy testing, we will utilize a clinically relevant metastatic orthotopic patient-derived xenograft model. Collectively, these studies will generate key preclinical data that will determine how human ligase inhibition can be successfully translated to improve survival outcomes for children with high-risk neuroblastoma.

-We will develop a targeted compound with selectivity towards DNA ligation activity for preclinical testing in a high-risk neuroblastoma model
-We will generate deliverables that will substantially contribute to advancing pediatric oncology research.