ABS 027: Emerging Glioblastoma Multiforme Therapeutics: Evaluating Interventional Clinical Trials and Hypoxia-Targeted Strategies

Ananya Uddanti ¹ , Paras Minhas ²

¹ Brown University
² Stanford University School of Medicine

Van Wickle (2025) Volume 1, ABS 027

Introduction: Glioblastoma multiforme (GBM) is an aggressive central nervous system malignancy with poor prognosis despite advances in multimodal treatment. This study systematically evaluates interventional GBM clinical trials to identify trends and limitations in therapeutic development. Clinical trials registered between January 1, 2012, and July 19, 2022, were screened for eligibility based on study phase (II-IV), interventional nature, and active, recruiting, or completed status. Of 1,728 GBM-related trials, 336 met inclusion criteria. A majority of trials were of open-label masking (89.58%, n=301), academia-sponsored (44.94%, n=151), and systemic interventions (87.20%, n=293). Despite an increasing trend in the number of trials initiated, other findings provided a basis for concern: (1) limited exploration of localized therapeutic strategies, (2) minimal funding by industry, and (3) widespread use of open-label masking. Lack of funding by industry and minimal trials examining localized therapies hinders the availability of interventions and the improvement of treatment techniques, respectively. Likewise, open-label masking is the supported standard for clinical trial studies, as it does not eliminate placebo responses. These conclusions are the basis of concerns and areas of improvement in the GBM clinical trial landscape. Given GBM’s hypoxic tumor microenvironment, hypoxia-inducible factors (HIF) play a pivotal role in tumor progression and therapeutic resistance. This study investigated HIF-2α inhibition as a novel therapeutic target by designing analogs of belzutifan, an FDA-approved HIF-2α inhibitor. Ligand preparation and molecular docking experiments assessed binding efficiency, Van der Waals interactions, and blood-brain barrier (BBB) permeability. While the designed analogs demonstrated comparable binding conformations to belzutifan, they did not exhibit significantly improved binding energies, nor did they enhance BBB permeability. This work contributes to the understanding of HIF-2α inhibition as a potential therapeutic approach for GBM and highlights the challenges in optimizing the design of analog drugs for improved efficacy.

Methods: A systematic analysis of clinical trials related to glioblastoma multiforme (GBM) was conducted using ClinicalTrials.gov. Trials were screened based on predefined inclusion and exclusion criteria. Trials that lacked relevance to GBM or did not provide sufficient information were excluded. A total of 147 trials were included for analysis. Key trial characteristics such as phase, funding source, intervention type (systemic vs. localized), sponsor affiliation, and masking design were recorded. Data were classified into categories to identify emerging therapeutic trends and gaps in clinical trial design. Interventions were further categorized by mechanism and classification. Trials were also evaluated for geographic and institutional representation to assess disparities in trial distribution and funding. The analysis aimed to assess not only the nature of GBM therapeutic development but also the broader clinical trial landscape and its implications for equitable care and innovation.

Results: We have demonstrated that systemic therapies dominate GBM clinical trials, comprising 87.2% (n=293) of interventions, with minimal exploration of localized strategies. Among the 336 trials analyzed, 44.94% (n=151) were sponsored by academic institutions, while industry-sponsored trials remained limited. Open-label masking was overwhelmingly common (89.58%, n=301), indicating a potential gap in trial design rigor. The majority of studies were Phase II trials, reflecting early-stage investigation with limited translation into late-stage clinical use. Despite increased trial activity over time, funding disparities and underrepresentation of novel or region-specific interventions continue to hinder progress in GBM treatment innovation.

Discussion: Our findings suggest that despite an upward trend in GBM clinical trial activity, the field remains limited by inadequate investment in localized therapies and low industry sponsorship. The predominance of open-label studies may undermine data rigor and generalizability. These disparities reveal persistent gaps in funding priorities and therapeutic innovation. Future directions should include incentivizing industry collaboration, supporting novel localized treatment strategies, and enhancing trial design quality. Broader molecular profiling and integration of biomarker-driven approaches may further improve therapeutic precision and patient outcomes. Addressing these challenges is essential to advancing GBM treatment and improving survival rates.