CTNI-17. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA

Abstract Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in early phase studies in H3 K27M-mutant DMG. In order to define response rates in H3 K27M DMG patients and to clarify the genomic, anatomic and molecular predictors of response, we performed an integrated pre-clinical and clinical analysis of ONC201 treatment. ONC201 was effective in intra-uterine electroporation (IUE)-generated H3 K27M-mutant murine glioma models with excellent CNS penetration and survival benefit. Patients with H3 K27M-mutant DMG treated with ONC201 on active clinical trials (n=50, 27 thalamic, 23 brainstem) showed an overall survival (OS) of 28.1 (range: 5.9–105) months from diagnosis (enrollment by 4/29/19, data cut-off 12/28/19), compared to historical median OS of 12 months. Median OS for non-recurrent patients has not been reached (n=16, median follow-up: 16.8 from diagnosis). For non-recurrent thalamic patients (n=8), median PFS is 20.1 (range: 9.3–27.6) months from diagnosis (median time on drug: 14.5 months). Best response for thalamic patients by RANO: 1 CR, 5 PR, 7 SD, 8 PD, 6 not reported. Decreased H3 K27M cell-free tumor DNA in plasma and CSF at 6 months correlated with long-term response. Baseline tumor gene expression profiling in patients treated with ONC201 (n=14) identified EGFR and the cortical developmental transcription factor FOXG1 as the strongest biomarkers of radiographic response to ONC201. Analysis of 541 ONC201-treated human cancer cell lines from DepMap, provided evidence for an EGFR-dependent ONC201 resistance mechanism. Analysis of 38 glioma cell lines further supports FOXG1 as a glioma-specific predictive biomarker of ONC201 response. The unprecedented survival results and radiographic responses to ONC201 in H3K27M DMG make a compelling case for later phase and combinatorial studies.

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Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells

Neuro-Oncology ◽

10.1093/neuonc/noaa283 ◽

2020 ◽

Author(s):

Erin R Bonner ◽

Sebastian M Waszak ◽

Michael A Grotzer ◽

Sabine Mueller ◽

Javad Nazarian

Keyword(s):

Drug Targets ◽

Molecular Mechanisms ◽

Human Cancer ◽

Meta Analysis ◽

Single Agent ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Mitochondrial Metabolism ◽

Response To Treatment ◽

Human Cancer Cell Lines

Abstract ONC201 is the first member of the imipridone family of anticancer drugs to enter the clinic for the treatment of diverse solid and hematologic cancers. A subset of pediatric and adult patients with highly aggressive brain tumors has shown remarkable clinical responses to ONC201, and recently, the more potent derivative ONC206 entered clinical trials as a single agent for the treatment of CNS cancers. Despite the emerging clinical interest in the utility of imipridones, their exact molecular mechanisms are not fully described. In fact, the existing literature points to multiple pathways (e.g. TRAIL signaling, dopamine receptor antagonism, and mitochondrial metabolism) as putative drug targets. We have performed a comprehensive literature review and highlighted mitochondrial metabolism as the major target of imipridones. In support of this, we performed a meta-analysis of an ONC201 screen across 539 human cancer cell lines and showed that the mitochondrial protease ClpP is the most significant predictive biomarker of response to treatment. Herein, we summarize the main findings on the anticancer mechanisms of this potent class of drugs, provide clarity on their role, and identify clinically relevant predictive biomarkers of response.

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