ONC201: a new treatment option being tested clinically for recurrent glioblastoma

Abstract

Glioblastoma is an aggressive central nervous system tumor with a 5-year-survival rate of less than 10%. Patients diagnosed with the disease are treated with surgery, radiation and temozolomide chemotherapy. Despite survival benefits, patients eventually relapse. There is a need for new treatments with improved efficacy. Imipridone ONC201 is a small molecule originally identified as a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound. ONC201 has the unique ability to induce expression of both pro-death ligand TRAIL and its receptor DR5 through engagement of the cellular integrated stress response (ISR) pathway. Arrillaga-Romany et al. report early results from futility analysis of a phase II clinical trial of ONC201 in 17 patients with recurrent or refractory glioblastoma conducted at the Massachusetts General Hospital Cancer Center. The results are promising, as ONC201 shows preliminary signs of efficacy. Further testing of ONC201 in an expansion cohort of patients with glioblastoma is ongoing.

Keywords: ONC201; clinical trial; glioblastoma.

Figure 1

Mechanism of action of ONC201 in glioblastoma. Small molecule ONC201 crosses the blood brain barrier and exerts it effects against glioblastoma bulk tumor cells and cancer stem cell-like (CSC) cells. ONC201 antagonizes dopamine receptors DRD2 and DRD3. The link between dopamine receptor antagonism by ONC201 and the downstream cell death signaling pathways perturbed by ONC201 is continuing to be unraveled. ONC201 dually inhibits phosphorylation of Akt and ERK, leading to the dephosphorylation of transcription factor FOXO3A. Dephosphorylated FOXO3A translocates into the nucleus where it activates transcription of its target genes, including pro-apoptotic death receptor ligand TNF-related apoptosis inducing ligand (TRAIL). ONC201 also activates the integrated stress response (ISR) through stimulation of EIF2a kinases. Phosphorylation of EIF2α leads to induction of transcription factors ATF4 and CHOP, which then increase DR5 expression. The combined upregulation of the ligand TRAIL and its surface receptor DR5 by ONC201 ultimately triggers cancer cell death.