Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma

Guisheng Zhao, Patrick Newbury, Yukitomo Ishi, Eugene Chekalin, Billy Zeng, Benjamin S. Glicksberg, Anita Wen, Shreya Paithankar, Takahiro Sasaki, Amreena Suri, Javad Nazarian, Michael E. Pacold, Daniel J. Brat, Theodore Nicolaides, Bin Chen, Rintaro Hashizume

Research output: Contribution to journalArticlepeer-review

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a 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. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.

Original languageEnglish
Pages (from-to)150
Number of pages1
JournalActa neuropathologica communications
Volume10
Issue number1
DOIs
StatePublished - 23 Oct 2022

Keywords

  • Computational approach
  • Diffuse intrinsic pontine glioma
  • Drug repurposing
  • Machine learning
  • Mycophenolate mofetil

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