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  • Abstract Bmi1 is a master regulatory stem cell self-renewal gene and epigenetic regulator that presents a downstream target of developmental pathways active during the genesis of the childhood brain tumor medulloblastoma (MB). Here, we describe Bmi1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a tumor that often presents with metastasis for which there is virtually no treatment option as children are limited to palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors, will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. By applying stem cell assays to primary and matched-recurrent Group 3 MB samples, we have identified Bmi1 as a key regulator of self-renewal that has the potential to drive treatment failure. We have shown Bmi1 to be enriched in treatment-refractory fractions in vivo and in vitro. 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 and when administered to mice xenografted with patient tumors. Oral administration of Bmi1 inhibitor in our MB patient-derived xenograft (PDX) model resulted in a marked reduction in both tumor burden, extent of spinal metastases and Bmi1 protein level in tumors post- in vivo therapy. Recurrent MB carries a mortality rate approaching 100%, and currently there exists no targeted therapy to treat recurrence. For the first time, we show that Bmi1 inhibition may present a genuine therapeutic strategy for recurrent childhood MB, inhibiting not only self-renewal but metastatic spread and spinal tumor dissemination. Selective targeting of MB stem cells using small molecules inhibitors against Bmi1 may further provide avenues for deescalating therapies that have devastating neurological and psychosocial sequela in children with MB.


  • Bakhshinyan, David
  • Garg, Neha
  • Manoranjan, Branavan
  • Venugopal, Chitra
  • Hallett, Robin
  • Wang, Xin
  • Kameda-smith, Michelle
  • Adile, Ashley
  • Ramaswamy, Vijay
  • Davis, Thomas
  • Weetall, Marla
  • Moon, Young-choon
  • Mitra, Siddhartha
  • Cho, Yoon-Jae
  • Taylor, Michael
  • Singh, Sheila

publication date

  • May 2017