EXTH-42. H3 K27M MUTANT GLIOMAS ARE SELECTIVELY KILLED BY ONC201, A SMALL MOLECULE INHIBITOR OF DOPAMINE RECEPTOR D2. (6th November 2017)

• Record Type: Journal Article
• Authors: Chi, Andrew S; Stafford, James M; Sen, Namita; Possemato, Richard; Placantonakis, Dimitris; Hidalgo, Eveline Teresa; Harter, David; Wisoff, Jeffrey; Golfinos, John; Arrillaga-Romany, Isabel; Batchelor, Tracy; Wen, Patrick; Wakimoto, Hiroaki; Cahill, Daniel; Allen, Joshua E; Oster, Wolfgang; Snuderl, Matija
• Is Part Of: Neuro-oncology. Volume 19(2017)Supplement 6
• Page Start: vi81
• Page End: vi81
• Publication Date: 2017-11-06
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nox168.334
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Histone H3 K27M mutations distinguish a subgroup of midline gliomas in children and young adults with devastating prognosis for which there are no effective medical therapies. In a recent phase 2 trial in adult recurrent glioblastoma with ONC201, a small molecule selective antagonist of the dopamine receptor D2 (DRD2) and D3 (DRD3), a 22 year old female with recurrent H3 K27M mutant glioblastoma had tumor regression of 92% that has persisted >15 months. Furthermore, antiseizure medication was discontinued and no ONC201 side effects were observed. Based on this exceptional response, we tested whether H3 K27M mutant gliomas were selectively sensitive to ONC201-induced apoptosis. METHODS: We tested the effect of ONC201 on the cell viability of a panel of patient-derived glioma tumorsphere lines, including four H3 K27M mutant diffuse intrinsic pontine gliomas (two HIST1H3B and two H3F3A mutant), two H3F3A G34R mutant glioblastomas, and five H3 K27M/G34R wildtype (2 pediatric, 3 adult) glioblastomas. We analyzed expression of DRD2, the target of ONC201, in adult glioblastoma (n=24), pediatric H3 K27M wildtype glioblastoma (n=3) and H3 K27M mutant glioblastoma (n=8) archival tumor tissue using RNASeq. RESULTS: ONC201 was most potently cytotoxic to H3 K27M mutant lines (median IC50 ~0.4 uM) and had modest activity against H3 K27M/G34R wildtype lines (median IC50 ~1.2 uM), while H3 G34R lines were relatively resistant (median IC50 > 10 uM). DRD2 expression was significantly increased in H3 K27M mutant glioblastoma archival tumors relative to H3 K27M wildtype adult/pediatric gliomas. CONCLUSIONS: H3 K27M mutant patient-derived glioma tumorspheres appear selectively sensitive to ONC201 in vitro. Expression of DRD2 is comparatively increased in H3 K27M mutant versus wildtype gliomas. Studies to further characterize the impact of DRD2 inhibition in H3 K27M mutant glioma are ongoing, however these preliminary data indicate ONC201 may have clinical utility in H3 K27M mutant gliomas.