Abstract 1613: β-lapachone: a novel targeted therapy for atypical teratoid rhabdoid tumors (ATRTs)

Abstract

Abstract Atypical teratoid rhabdoid tumors (ATRTs) are aggressive malignant neoplasms that occur in the CNS, most commonly in children <3 years of age. Despite intensive chemo-radiotherapy and surgery, the outcomes for patients with this disease remain dismal, with ∼75% of patients dying from their disease at a median of 10 months after diagnosis. Thus, it is critical to identify and validate novel ATRT targets for new therapies. We found that the pathognomonic genetic lesion of ATRTs, loss of the SWI/SNF chromatin remodeling complex member INI1/hSNF5/SMARCB1, leads to high expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), a two-electron oxidoreductase. Thus, we hypothesized that ATRTs will be vulnerable to drugs, such as ß-lapachone (ß-lap, ARQ761 in clinical form), that selectively kill NQO1-expressing cells. A panel of ATRT cell lines exhibited overall high NQO1 expression and low micromolar sensitivity to ß-lap (IC50 1.6-4 uM), with the exception of cell lines that were homozygous for the C609T NQO1 (*2) polymorphism, which exhibited no NQO1 activity and were resistant to ß-lap treatment (IC50 >15 uM). A two-hour pulse with ß-lap caused a burst of ROS-mediated DNA damage and PARP1 hyperactivation, resulting in NAD+ and ATP depletion and caspase-independent, mu-calpain-mediated apoptosis. Co-treatment with dicoumarol, a specific inhibitor of NQO1, prevented these effects by blocking the NQO1-dependent bioactivation of ß-lap. Low expression of NQO1 in normal brain and other pediatric tissues suggests a wide therapeutic window for ß-lap. These findings encourage the continued study of ß-lap and other NQO1 bioactivated therapeutics for the treatment of this recalcitrant disease. This work was supported by NIH/NCI R01 CA102972 to DAB and a REACH award from the Alex's Lemonade Stand Foundation to JFA and TWL. Citation Format: Zachary R. Moore, Sarai Stuart, Agnieszka Cholka, Ashwin Venkataraman, Jingying Xu, Anat Erdreich-Epstein, Dinesh Rakheja, David A. Boothman, James F. Amatruda, Theodore W. Laetsch. β-lapachone: a novel targeted therapy for atypical teratoid rhabdoid tumors (ATRTs). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1613. doi:10.1158/1538-7445.AM2015-1613