Path-13. Molecular and Biology Correlative Results From the Phase 1b Trial of Unesbulin (ptc596) With Radiotherapy in Children Newly-diagnosed With Diffuse Intrinsic Pontine Glioma (dipg) and High-grade Glioma (hgg): a Report From the Collaborative Network for Neuro-oncology Clinical Trials (connect)
Year: 2024
Type: conference-abstract
Abstract: BACKGROUND Within the CONNECT1702 trial of unesbulin (tubulin-binding agent causing BMI-1 modulation) with radiotherapy in patients with DIPG/HGG, tumor tissue was analyzed at diagnosis and/or autopsy for biology correlatives, enabling comprehensive, longitudinal molecular characterization. METHODS Whole genome sequencing, RNA-sequencing, and Western blot analyses were performed on tumor, normal brain, and peripheral blood mononuclear cells (PBMCs). RESULTS Tumor tissue from diagnosis (n=11) and/or autopsy (n=7) was analyzed for 16 patients (DIPG=9; HGG=7). Western blot analyses demonstrated 1) BMI-1 overexpression in baseline tumor compared to normal brain and 2) primary on-target effect of BMI1-modulation causing M-phase mitotic arrest when comparing pre- and post-treated PBMCs (increased H3S10-phosphorylation). Among 9 DIPG patients, alterations in the following genes were identified: H3-3A (H3.3) (n=5), H3C2 (H3.1) (n=2, both with co-occurring ACVR1 and PIK3CA mutations), TP53 (n=5), ATRX (n=2), and PPM1D (n=2). Tumors from two longer DIPG survivors were H3.1-, ACVR1-mutant (overall survival [OS]=26 months) and MET-amplified (OS=18 months); one patient with H3.3K27M-DIPG had germline MSH6 mutation (Lynch syndrome) (OS=12.6 months). Among 7 HGG patients, alterations in the following genes were identified: H3-3A (n=5), TP53 (n=3), NF1 (n=3), PDGFRA (n=1), EGFR (n=1), and PIK3CA (n=1). A BRAFV600E mutation was observed in the thalamic HGG patient (H3.3K27M) with greatest progression-free survival (>23 months). Early leptomeningeal metastases occurred in one DIPG patient with BCOR alteration and one HGG patient, with MYCN amplification identified in the spinal metastasis, but not intracranial disease. From gene set enrichment analyses, pathways enriched in patients with longer survival included telomerase regulation and ATP synthesis, whereas pathways enriched in patients with shorter survival included interneuron development, neuron semaphorin signaling, and gamma aminobutyric signaling. CONCLUSIONS Comprehensive molecular profiling of diagnostic and post-mortem tumor tissue provides valuable early biological insight, elucidating potential genomic biomarkers predictive of outcome and response to M-phase alteration and BMI-1 modulation in DIPG/HGG.
Source: Neuro-Oncology
Authors: Margot Lazow, Patricia Baxter, Shiva Senthil Kumar, Maya Mohamad, Alan Mackay, Joseph Stanek, Diana Rodriguez, Joshua Palmer, James Leach, Leonie Mikael, Diana Thomas, Christine Fuller, Daniel Boué, Christopher Pierson, John Breneman, Xiao-Nan Li, Ralph Salloum, David Ashley, Peter de Blank, Eugene Hwang, Sarah Leary, Ashley Plant, Michael Fisher, Susan Chi, Mythili Murala, Marla Weetall, Mark Rance, John Baird, Dhiren D’Silva, Kylie O’Keefe, Jeffrey Leonard, Clinton Stewart, Chris Jones, Elaine Mardis, Maryam Fouladi, Rachid Drissi
Institutions: Nationwide Children's Hospital, Texas Children's Hospital, Institute of Cancer Research, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Cincinnati Children's Hospital Medical Center, SUNY Upstate Medical University, Lurie Children's Hospital, Duke Children's Hospital & Health Center, Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, Boston Children's Hospital, PTC Therapeutics (United States), St. Jude Children's Research Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4404236983