Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas Journal Article

   


Authors: Wang, Y.; Wild, A. T.; Turcan, S.; Wu, W. H.; Sigel, C.; Klimstra, D. S.; Ma, X.; Gong, Y.; Holland, E. C.; Huse, J. T.; Chan, T. A.
Article Title: Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas
Abstract: Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5′-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers. © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Keywords: radiotherapy; tumorigenesis; radiation effects; tumors; cholangiocarcinoma; diseases; isocitrate dehydrogenase; multimodality therapy; global change; diphosphates; therapeutic effects; co treatments
Journal Title: Science Advances
Volume: 6
Issue: 17
ISSN: 2375-2548
Publisher: Amer Assoc Advancement Science  
Date Published: 2020-04-22
Start Page: aaz3221
Language: English
DOI: 10.1126/sciadv.aaz3221
PROVIDER: scopus
PMCID: PMC7176409
PUBMED: 32494639
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85084652134&doi=10.1126%2fsciadv.aaz3221&partnerID=40&md5=eaceec96c8eb34183a3e6b870c78ae3e
Notes: Article -- Export Date: 1 June 2020 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    317 Chan
  2. David S Klimstra
    978 Klimstra
  3. Yongxing Gong
    10 Gong
  4. Carlie Selbo Sigel
    116 Sigel
  5. Wei Hang Wu
    11 Wu
  6. Aaron Tyler Wild
    19 Wild
  7. Yuxiang Wang
    10 Wang
  8. Xiaoxiao Ma
    5 Ma
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