Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33

Saritha Tantravedi; Farhad Vesuna; Paul T Winnard Jr; Allison Martin; Michael Lim; Charles G Eberhart; Cynthia Berlinicke; Eric Raabe; Paul J van Diest; Venu Raman

doi:10.1016/j.tranon.2018.09.002

Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33

Transl Oncol. 2019 Jan;12(1):96-105. doi: 10.1016/j.tranon.2018.09.002. Epub 2018 Oct 3.

Authors

Affiliations

¹ Division of Cancer Imaging Research, Department of Radiology and Radiology Science, Johns Hopkins University, School of Medicine, Baltimore, MD.
² Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD.
³ Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD.
⁴ Department of Pathology and Oncology, Johns Hopkins Hospital, Baltimore, MD.
⁵ Wilmer Eye Institute, Johns Hopkins University, School of Medicine, MD.
⁶ Department of Pediatric Oncology and Pathology, Johns Hopkins Hospital, Baltimore, MD.
⁷ Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸ Division of Cancer Imaging Research, Department of Radiology and Radiology Science, Johns Hopkins University, School of Medicine, Baltimore, MD; Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: vraman2@jhmi.edu.

Abstract

Medulloblastoma is the most common malignant tumor that arises from the cerebellum of the central nervous system. Clinically, medulloblastomas are treated by surgery, radiation, and chemotherapy, all of which result in toxicity and morbidity. Recent reports have identified that DDX3, a member of the RNA helicase family, is mutated in medulloblastoma. In this study, we demonstrate the role of DDX3 in driving medulloblastoma. With the use of a small molecule inhibitor of DDX3, RK-33, we could inhibit growth and promote cell death in two medulloblastoma cell lines, DAOY and UW228, with IC50 values of 2.5 μM and 3.5 μM, respectively. Treatment of DAOY and UW228 cells with RK-33 caused a G1 arrest, resulted in reduced TCF reporter activity, and reduced mRNA expression levels of downstream target genes of the WNT pathway, such as Axin2, CCND1, MYC, and Survivin. In addition, treatment of DAOY and UW228 cells with a combination of RK-33 and radiation exhibited a synergistic effect. Importantly, the combination of RK-33 and 5 Gy radiation caused tumor regression in a mouse xenograft model of medulloblastoma. Using immunohistochemistry, we observed DDX3 expression in both pediatric (55%) and adult (66%) medulloblastoma patients. Based on these results, we conclude that RK-33 is a promising radiosensitizing agent that inhibits DDX3 activity and down-regulates WNT/β-catenin signaling and could be used as a frontline therapeutic strategy for DDX3-expressing medulloblastomas in combination with radiation.

Grants and funding

UL1 TR001079/TR/NCATS NIH HHS/United States