|
|||||
|
|
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
|
| Authors: | Mark Barszczyk Pawel Buczkowicz Pedro Castelo-Branco Stephen C. Mack Vijay Ramaswamy Joshua Mangerel Sameer Agnihotri Marc Remke Brian Golbourn Sanja Pajovic Cynthia Elizabeth Man Yu Betty Luu Andrew Morrison Jennifer Adamski Kathleen Nethery-Brokx Xiao-Nan Li Timothy Van Meter Peter B. Dirks James T. Rutka Michael D. Taylor Uri Tabori Cynthia Hawkins |
| Affiliation: | 1. The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada 2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada 3. Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada 4. Regenerative Medicine Program, Department of Medicine and Biomedical Sciences, Centre for Molecular and Structural Biomedicine, CBME/IBB, University of Algarve, Faro, Portugal 5. Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada 6. Brain Tumor Program, Texas Children’s Cancer Center, Houston, TX, USA 7. Division of Pediatric Hematology-Oncology, Virginia Commonwealth University, Richmond, VA, USA 8. Division of Surgery, The Hospital for Sick Children, Toronto, ON, Canada |
| Abstract: | Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas. |
| Keywords: | |
| 本文献已被 SpringerLink 等数据库收录！ | |