Abstract
INTRODUCTION
ONC201 is a highly selective antagonist of dopamine receptor D2 (DRD2) that is in phase II clinical trial as treatment for recurrent glioblastoma. Here we examine the molecular determinants of therapeutic response that are associated with long-term survivors.
METHODS
Immuno-histochemical (IHC) analysis/pathway-based transcriptomal analysis of clinical glioblastoma specimens, in vitro- and in vivo-studies of dopamine antagonist inhibition, analysis of glioblastoma specimens in patients treated with the dopamine receptor antagonist, ONC201.
RESULTS
In IHC of clinical glioblastoma samples, we found that the expression of dopamine receptor 2 (DRD2) coincides with EGFR over-expression in mesenchymal and classical glioblastomas. In contrast, DRD2 over-expression was found in proneural and neural glioblastomas in the absence EGFR over-expression. These patterns of expression were recapitulated in The Cancer Genome Atlas (TCGA) as well patient derived glioblastoma (PDX) lines. In vitro and in vivo, mesenchymal glioblastoma PDX lines with high expression of EGFR and DRD2 were refractory to DRD2 or EGFR inhibition; simultaneous EGFR and DRD2 inhibition were required to arrest the growth of these mesenchymal glioblastomas. In contrast, proneural glioblastoma lines with high DRD2 expression (and low EGFR expression) were exquisitely sensitive to dopamine antagonists in vitro and in vivo (in subcutaneous and intracranial models). Importantly, proneural glioblastoma lines with high DRD2 expression secrete high levels of dopamine, creating autocrine mitogenic signaling that drive glioblastoma growth. In clinical samples derived from a Phase 2 clinical trial where recurrent glioblastoma patients were treated with the DRD2 antagonist, ONC201, long-terms survival (>2 years survival after glioblastoma recurrence) was observed only in patients afflicted with glioblastomas characterized by low EGFR and high DRD2 expression.
CONCLUSION
Our data suggest that DRD2 signaling is essential in glioblastomas that are not mitogenically driven by EGFR signaling. These tumors appear exquisitely sensitive to ONC201 mediated DRD2 inhibition.