DIPG-49. STAT3 AS A THERAPEUTIC TARGET IN DIPG. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Olaciregui, Nagore G; Carvalho, Diana; Mackay, Alan; Pascual-Pasto, Guillem; Clarke, Matthew; Molinari, Valeria; Izquierdo, Elisa; Goncalves, Jordan; Courbebaisse, Yann; La Madrid, Andres Morales; Suñol, Mariona; Cruz, Ofelia; Mora, Jaume; Jones, Chris; Carcaboso, Angel M
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i58
• Page End: i59
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.142
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Diffuse intrinsic pontine glioma (DIPG) is characterized by the infiltration and migration of tumor cells within the brain parenchyma. The signal transduction protein STAT3, activated by phosphorylation to phospho-STAT3 (p-STAT3), promotes tumor migration and invasion in many cancer types including gliomas. Thus, we hypothesized that the STAT3 pathway might be involved in the pathogenesis of DIPG. Re-analyzing publicly available gene expression data from 220 pediatric high grade gliomas of which 65 were DIPG, we found that STAT3 upregulation correlated with worse overall survival (p= 0.0099, log-rank test). Using immunohistochemistry and immunoblotting we showed that p-STAT3 was positive in DIPG necropsies and patient-derived cells. Treatment with the STAT3 inhibitor WP1066 led to the inhibition of cell proliferation in DIPG cultures, with IC50 values ranging 0.66–5.5 µM. Sub-cytotoxic concentrations of WP1066 downregulated p-STAT3 and inhibited cell migration in HSJD-DIPG-007 cells ( H3F3A K27M, ACVR1 R206H). Treatment of HSJD-DIPG-007 tumor-bearing mice with WP1066 (40 mg/kg every two days for a total of 8 days) extended the median survival of the animals when compared to vehicle (73 versus 82 days, p= 0.045, log-rank test). Upon completion of the therapy treated mice showed less tumor burden and decreased p-STAT3 levels as compared to untreated ones. Drug efficacy could be explained by good CNS penetration since WP1066 reached active concentrations in the tumor (5.8 µM at 0.5 h after one dose of 40 mg/kg). Our results suggest that the STAT3 pathway might be a relevant therapeutic target in DIPG.