EXTH-30. HARNESSING CELLULAR STRESS FOR IMMUNE TARGETING OF DIPGS. (12th November 2021)

• Record Type: Journal Article
• Authors: Gopalakrishnan, Vidya; Sharma, Ajay; Sridharan, Sreepradha; Cheng, Donghang; Bournat, Juan; Shaik, Shavali; Harmanci, Arif; Siddaway, Robert; Dobson, Tara; Swaminathan, Jyothishmathi; Allen, Joshua; Hawkins, Cynthia; Khatua, Soumen; Xu, Lin; Zaky, Wafik
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi169
• Page End: vi170
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.669
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. An almost ubiquitous dominant negative mutation at lysine (K)-27 in genes encoding histone genes HIST1H3B and H3F3A found in patient tumors is a driver of DIPG development. ONC201, a small molecule DRD2 antagonist and ClpP agonist developed by Chimerix Inc, targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling. It is under clinical investigation in patients with recurrent H3K27M DMGs. In adults, single agent studies have shown durable objective responses when administered orally. A multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) for pediatric patients with H3K27M DMGs is open and accruing. Preliminary results suggest that the drug has a favorable safety profile and holds promise for patients with DIPGs and other midline gliomas. However, the mechanism of action of ONC201 against DIPGs warrants further study. Here, we show that ONC201 is cytotoxic to DIPGs in vitro and in vivo . RNA Seq analyses revealed cell context specific deployment of PERK-activated UPR and calcium signaling-associated RON tyrosine kinase-macrophage stimulating protein (MSP) signaling in DIPGs. Single cell proteomic assays revealed substantial heterogeneity in the sensitivity of DIPG cells to ONC201, and identified stem-like sub-populations of H3K27M DIPGs with intrinsic insensitivity to the drug. ONC201 treatment, which induces cellular stress, also sensitized DIPG cells to cytolytic activity by ex-vivo expanded and activated innate immune cells, in vitro. Ongoing in vivo experiments are expected to support a novel investigational study in patients with midline gliomas.