Skip to main content Accessibility help
×
Home

PS1 - 170 Bmi1 is a Therapeutic Target in Recurrent Childhood Medulloblastoma

  • N. Garg (a1), D. Bakhshinyan, B. Manoranjan, C. Venugopal, R. Hallett, S. Mahendram, T. Vijayakumar, M. Subapanditha, M. Qazi, M. Singh, N. McFarlane, A. Mann, P. Vora, T. Davis and S. Singh...

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumour, and is categorized into four molecular subgroups, with Group 3 MB having the worst prognosis due to the highest rate of metastatic dissemination and relapse. In this work, we describe the epigenetic regulator Bmi1 as a novel therapeutic target for treatment of recurrent Group 3 MB. Through comparative profiling of primary and recurrent MB, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. We have optimized an in vivo mouse-adapted therapy model that has the advantage of generating recurrent, human, treatment-refractory MBs. Our preliminary studies showed that although chemoradiotherapy administered to mice engrafted with human MB showed reduction in tumour size, Bmi1 expression was enriched in the post-treatment residual tumour. Furthermore, we found that knockdown of Bmi1 in human recurrent MB cells decreases proliferation and self-renewing capacities of MB cells in vitro as well as both tumour size and extent of spinal leptomeningeal metastases in vivo. Oral administration of a potent Bmi1 inhibitor, PTC 028, resulted in a marked reduction in tumour burden and an increased survival in treatment cohort. Bmi1 inhibitors showed high specificity for MB cells and spared normal human neural stem cells, when treated with doses relevant for MB cells. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious agent such as Bmi1 inhibitor could be rapidly transitioned to clinical trials.

    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      PS1 - 170 Bmi1 is a Therapeutic Target in Recurrent Childhood Medulloblastoma
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      PS1 - 170 Bmi1 is a Therapeutic Target in Recurrent Childhood Medulloblastoma
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      PS1 - 170 Bmi1 is a Therapeutic Target in Recurrent Childhood Medulloblastoma
      Available formats
      ×

Copyright

Corresponding author

PS1 - 170 Bmi1 is a Therapeutic Target in Recurrent Childhood Medulloblastoma

  • N. Garg (a1), D. Bakhshinyan, B. Manoranjan, C. Venugopal, R. Hallett, S. Mahendram, T. Vijayakumar, M. Subapanditha, M. Qazi, M. Singh, N. McFarlane, A. Mann, P. Vora, T. Davis and S. Singh...

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed