Endothelin 3/Endothelin Receptor B Signaling Pathway Blockade Depletes Radio-Chemoresistant Glioblastoma Stem Cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Patients with glioblastoma multiforme (GBM) despite being treated with gross total resection and post-operative temozolomide (TMZ) plus radiation therapy (RT), will almost always develop tumor recurrence. Hypothesis and objective: We hypothesize GBM stem cells (GSC) are responsible for post-treatment tumor recurrence and blockade of endothelin-3 (EDN3)/endothelin receptor B(EDNRB) signaling, a signaling pathway for neural crest development that hyperactivated in GSC, will enhance TMZ/RT treatment efficacy for GSC. Materials and Methods: Patient tumor-derived GSC were seeded at clonal density and subjected to radiochemotherapy at dose and schedule comparable to patient treatment. Treatment efficacy and synergy of EDNRB antagonist (BQ788) plus TMZ/RT were evaluated by the clonogenic efficiency, cell proliferation, and cell apoptosis of GSCs. Results: GSC are resistant to TMZ treatment alone (10μM), while treatment with BQ788 (75μM) alone can restrict cell migration, decrease clonogenic efficiency, and induce cell apoptosis. The RT displays the highest treatment efficacy on GSC when compared to TMZ or BQ788 alone and addition of TMZ to RT is slightly synergistic. Although only few small tumor spheres were detected when treated with RT or RT/TMZ, the survival clones regain proliferative activity and possess enhanced clonogenicity and anti-apoptotic ability when compared to untreated GSC. Treatment efficacy was greatly improved when GSC treated with BQ788 combined with RT/TMZ and no cells with self- renewal capacity were detected or recovered from the treatment. Conclusion: Subsets of GSC clones are resistance to standard RT/TMZ treatment and possess enhanced tumor sphere-forming capacity. Incorporate EDN3/EDNRB antagonist to a standard radiochemotherapy provide a significant treatment synergy in depletion of functional GSC and thus highlights a novel therapeutic strategy for the prevention of GSC-mediated tumor occurrence and recurrence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3308. doi:10.1158/1538-7445.AM2011-3308