EXTH-36. COMBINING ONC201 AND PAXALISIB FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA (DMG); THE PRECLINICAL RESULTS UNDERPINNING THE INTERNATIONAL PHASE II CLINICAL TRIAL (NCT05009992)
Authors: Jackson Evangeline , Duchatel Ryan , Staudt Dilana , Persson Mika , Mannan Abdul , Yadavilli Sridevi , Parackal Sarah , Game Shaye , Chong Wai Chin , Jayasekara W Samantha , Grand Marion Le , Kearney Padraic , Douglas Alicia , Findlay Izac , Germon Zacary , McEwen Holly , Beitaki Tyrone , Patabendige Adjanie , Skerrett-byrne David , Nixon Brett , Smith Nathan , Day Bryan , Manoharan Neevika , Nagabushan Sumanth , Hansford Jordan , Govender Dinisher , McCowage Geoffrey , Firestein Ron , Howlett Meegan , Endersby Raelene , Gottardo Nicholas , Alvaro Frank , Waszak Sebastian , Larsen Martin , Sanguino Yolanda Colino , Valdes-Mora Fatima , Rakotomalala Andria , Meignan Samuel , Pasquier Eddy , Andre Nicolas , Hulleman Esther , Eisenstat David , Vitanza Nicholas , Nazarian Javad , Koschmann Carl , Mueller Sabine , Cain Jason , Dun Matthew 
Published: November 2023

Diffuse midline gliomas (DMGs) diagnosed in the pons (DIPG) are universally fatal central nervous system tumors and are the leading cause of cancer-related death in children. Palliative radiotherapy is the only recognized treatment, with median overall survival just 9-11 months. The brain-penetrant, small molecule, ONC201, shows early-stage clinical trial efficacy, extending survival by ~9-11 months compared to historic controls. However, studies to determine the mechanisms behind the temporary clinical response to ONC201 are needed. Here, we have used a systems-biological approach to investigate whether genomic features influenced ONC201 response. DMGs harboring PIK3CA mutations were more sensitive to ONC201, whereas those harboring TP53 mutations were less sensitive. Quantitative proteogenomics identified that ONC201 elicits potent agonism of the mitochondrial protease, ClpP, driving proteolysis of electron transport chain and tricarboxylic acid proteins, leading to mitochondrial dysfunction. However, metabolic adaptation to ONC201 is promoted by the spare redox-signaling capacity of cells harboring WT-PIK3CA that was counteracted using the brain-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. ONC201 and paxalisib combinations extended survival of orthotopic DIPG xenograft mouse models (SU-DIPG-VI, p=0.0027; SF8626, p=0.0002; HSJD-DIPG-007, p=&lt; 0.0001). The combination in the first three recorded patients; two at progression following re-irradiation, and one at diagnosis following the completion of radiation, resulted in dramatic reductions in tumor area, dramatically extending overall survival for all three patients (25 months, 30 and 31 months continuing). The DIPG patient receiving the combination since diagnosis, remains in progression free survival (MR axial diagnosis scan = 1554 mm2, current tumour area = 306 mm2, ~80% reduction). The patient continuing to receive the combination at progression and following reirradiation also experienced a marked decrease in tumor size (MR axial diagnosis scan = 1248 mm2, current tumour area = 315 mm2, ~75% reduction), 10 months following radiological detection of progression. These data inform the phase II clinical trial (NCT05009992).