DIPG-19. REVERSAL OF CANCER GENE EXPRESSION IDENTIFIES NOVEL THERAPEUTICS FOR DIFFUSE INTRINSIC PONTINE GLIOMA. (23rd April 2019)

• Record Type: Journal Article
• Authors: Zhao, Guisheng; Newbury, Patrick; Zeng, William; Muldoon, Daniel; Glicksberg, Benjamin S; Wen, Anita; Liu, Ke; Chen, Bin; Nicolaides, Theodore
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii72
• Page End: ii72
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.040
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is an aggressive type of brainstem cancer that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. To identify potential therapeutic agents, we used a recently developed computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. METHODS: We used a systematic computational approach with publicly available databases of gene expression signatures in DIPG, as well as gene expression data of cancer cell lines before and after treatment in conjunction with a massive library of clinically available drugs. We identified three drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. We used three DIPG cell lines (SF8628, DIPG4, DIPG-NYU) along with immortalized normal human astrocytes (NHA) as control to test these drugs. Flow cytometry, immunoblot analysis, viability assays, and RNA-Seq before and after drug treatment were performed. In vivo experiments are currently underway. RESULTS: All three drugs showed potency against the primary DIPG4 cell line compared to NHA control. Triptolide showed the most potency against primary DIPG cell lines bearing H3K27M mutations (SF8628 and DIPG4, with IC50's in the nanomolar range after 72 hours treatment), while the effect on DIPG cell line without H3K27M mutation (DIPG-NYU) was less potent. Immunoblot data also suggested a correlation between drug potency and H3K27M levels in these cell lines. CONCLUSION: Using a computational approach, we identified clinically available drugs with the ability to reverse DIPG gene expression signatures and significantly decreased the growth rate of primary DIPG cells in vitro . This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.