Functional genomics identifies therapeutic options, biomarkers, and resistance mechanisms for high-grade gliomas
High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor <i>ex vivo</i> and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation.
Authors
- Ryan Feathers
- Panos Z. Anastasiadis (ORCID: https://orcid.org/0000-0003-4436-9435)
- Terry C. Burns (ORCID: https://orcid.org/0000-0001-7633-3045)
- Stephen James Murphy
- Janet Schaefer-Klein
- Sotiris Sotiriou (ORCID: https://orcid.org/0000-0002-6060-4995)
- Christiane M. Ida
- Lindsey Kinsella
- George Vasmatzis (ORCID: https://orcid.org/0000-0002-3401-3497)
- Kurt A. Jaeckle (ORCID: https://orcid.org/0000-0002-7827-463X)
- Marcela Salomao (ORCID: https://orcid.org/0000-0002-3631-2407)
- Steven Rosenfeld
- Angela Emanuel
- Sarah H. Johnson (ORCID: https://orcid.org/0000-0001-7412-5322)
- Diogo Moniz‐Garcia (ORCID: https://orcid.org/0000-0002-3654-3387)
- A. Quiñones-Hinojosa
- Farhad Kosari (ORCID: https://orcid.org/0000-0003-0321-164X)
- Aaron S. Mansfield (ORCID: https://orcid.org/0000-0002-9483-6903)
- Alyx B. Porter (ORCID: https://orcid.org/0000-0003-0666-1320)
- James B. Smadbeck (ORCID: https://orcid.org/0000-0002-8902-0950)
- Michael T. Barrett (ORCID: https://orcid.org/0000-0002-5646-1530)
- Dorsay Sadeghian
- John C. Cheville (ORCID: https://orcid.org/0000-0002-8202-6268)
- Maciej Mrgula
- Lauren E. Haydu
- Faye R. Harris
- Wendy Sherman
- Lin Yang (ORCID: https://orcid.org/0009-0005-6756-1683)
- Alexa McCune
- Mitesh Borad
- Sani H. Kizilbash
- Shannon P. Fortin Ensign
- Wan-Hsin Lin
- Taylor Berry
- Leila A. Jones
- Jamie Hall
- Bernard R. Bendok
Institutions
- Mayo Clinic (US)
- WinnMed (US)
- Mayo Clinic in Arizona (US)
- Mayo Clinic Hospital (US)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-03
- DOI
- https://doi.org/10.64898/2026.02.01.701806
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00