2026 Poster Presentations
P037: HYPOXIA-TARGETED THERAPEUTIC STRATEGIES IN GLIOBLASTOMA: A NARRATIVE REVIEW OF EMERGING CLINICAL AND PRECLINICAL EVIDENCE
Jawad A Saad, BS; James Chung, BS; Ahmad Kafri, BS; Julien Rossignol, PhD; Maxwell Verbrugge, MD; Jesse Bakke, PhD; Central Michigan University College of Medicine
Introduction: Glioblastoma multiforme (GBM) is an aggressive cancer associated with notoriously poor clinical outcomes. The characteristic resistance of GBM to standard treatments is closely linked to its capacity for metabolic reprogramming. This metabolic shift often results in a severely dysfunctional tumor microenvironment characterized by chronic hypoxia. Hypoxic conditions stabilize and activate Hypoxia-Inducible Factor-1α (HIF-1α), a transcription factor that promotes cellular pathways influencing proliferation and malignant progression, further exacerbating therapy resistance. This review summarizes novel therapeutic approaches designed to reverse or exploit these metabolic and hypoxic vulnerabilities.
The aim of this analysis is to evaluate emerging strategies, drawing on preclinical and clinical trial data, that target GBM's core metabolic dependencies and the resulting hypoxia to assess their potential in overcoming resistance and improving patient outcomes.
Methods: A narrative review was conducted, synthesizing 152 peer-reviewed publications from January 2000 to September 2025 across basic, translational, and clinical studies. Literature was identified through PubMed, Embase, and Web of Science using terms related to glioblastoma metabolism and hypoxia-driven signaling (HIF-1α/HIF-2α, angiogenesis, metabolic therapy). Reference lists of key articles were also reviewed to capture additional publications. Eligible studies included English-language articles focused on GBM, encompassing preclinical models, translational work, and clinical trials, while excluding single case reports and non-primary brain tumor studies. Findings were thematically grouped by mechanism, with this section of the study focusing on hypoxia-directed interventions, including hypoxia-activated prodrugs (HAP), hyperbaric oxygen therapy (HBOT), oxygen transport agents (OTA), and small-molecule inhibitors
Results: Clinical investigation into these hypoxia-targeting therapies shows promising preliminary efficacy. Evofosfamide, a HAP that releases a cytotoxic agent in low-oxygen environments, was studied in combination with bevacizumab (Bev) for recurrent Bev-refractory GBM. The combined therapy was tolerable and yielded a 17.4% overall response rate with disease control in 60.9% of patients. Imaging analysis indicated that decreased hypoxic volumes were inversely correlated with longer overall and progression-free survival. HBOT, which increases oxygen supply, achieved a median overall survival (OS) of up to 22.1 months when combined with daily radiotherapy (RT) and multi-agent chemotherapy in Phase II trials for high-grade gliomas. HBOT enhances chemosensitivity by reducing the expression of HIF-1α/HIF-2α and the drug efflux transporter ABCG2. The OTA, trans-sodium crocetinate (TSC), showed long-term results where 36% of patients receiving the full dose were alive at 2 years when combined with concomitant RT and Temozolomide. Additionally, Noscapine, a small-molecule inhibitor capable of crossing the blood-brain barrier (BBB), has demonstrated the ability to inhibit HIF-1α nuclear accumulation and transcription, thereby suppressing tumor growth.
Conclusion: Targeting the core vulnerability of metabolic reprogramming, particularly hypoxia, through combination approaches (HAPs, HBOT, OTAs, and inhibitors) represents a vital direction for GBM therapy development. While these strategies demonstrate encouraging safety profiles and preliminary efficacy, challenges posed by tumor heterogeneity and inadequate drug penetration across the BBB must be addressed. Further randomized studies are necessary to optimize the integration of these metabolic interventions into personalized treatment regimens for GBM patients.