BMI1 is a therapeutic target in recurrent medulloblastoma Conference Paper uri icon

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abstract

  • Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.

authors

  • Bakhshinyan, David
  • Venugopal, Chitra
  • Adile, Ashley A
  • Garg, Neha
  • Manoranjan, Branavan
  • Hallett, Robin
  • Wang, Xin
  • Mahendram, Sujeivan
  • Vora, Parvez
  • Vijayakumar, Thusyanth
  • Subapanditha, Minomi
  • Singh, Mohini
  • Kameda-Smith, Michelle Masayo
  • Qazi, Maleeha
  • McFarlane, Nicole
  • Mann, Aneet
  • Ajani, Olufemi A
  • Yarascavitch, Blake
  • Ramaswamy, Vijay
  • Farooq, Hamza
  • Morrissy, Sorana
  • Cao, Liangxian
  • Sydorenko, Nadiya
  • Baiazitov, Ramil
  • Du, Wu
  • Sheedy, Josephine
  • Weetall, Marla
  • Moon, Young-Choon
  • Lee, Chang-Sun
  • Kwiecien, Jacek M
  • Delaney, Kathleen
  • Doble, Bradley
  • Cho, Yoon-Jae
  • Mitra, Siddhartha
  • Kaplan, David
  • Taylor, Michael D
  • Davis, Thomas W
  • Singh, Sheila

publication date

  • March 2019

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