Glioblastoma Has Defied Treatments.
It's Time for a Radically Different Approach
Despite decades of incremental surgical innovation — from awake craniotomy to intraoperative MRI to fluorescence-guided resection — glioblastoma remains among the most therapeutically resistant malignancies in oncology. This post examines the current standard of care, the state of the surgical art, and the biological problem that remains unsolved.
Glioblastoma multiforme (GBM) represents the most common and aggressive primary malignant brain tumor, accounting for approximately half of all malignant central nervous system cancers. Despite being a rare disease — with roughly 15,000 new cases diagnosed in the United States each year — it carries a disproportionate burden of morbidity and mortality. Median overall survival with optimal treatment remains 12 to 18 months, a figure that has not significantly changed over the past two decades.
Glioblastoma is the central focus of UP Oncolytics' therapeutic program. Our platform is built on wild-type Zika virus (ZIKV) strains that naturally cross the blood-brain barrier, are minimally neurovirulent, and exhibit selective tropism for glioblastoma stem cells. Before describing that mechanism, it is useful to examine the current standard of care: what it achieves, how far it has advanced, and where fundamental limitations persist.
The Stupp Protocol: What Standard of Care Looks Like
The current standard of care for newly diagnosed GBM has been defined by the Stupp protocol since 2005: maximal safe surgical resection, followed by concurrent radiotherapy (60 Gy over six weeks) and temozolomide (TMZ) chemotherapy, then adjuvant TMZ for six additional months. For patients whose tumors carry MGMT promoter methylation — a marker of chemosensitivity — outcomes are modestly better. For the majority who lack it, the benefit of TMZ is marginal.
In 2015, the addition of tumor-treating fields (TTF) via the Optune device was incorporated into standard practice for newly diagnosed GBM following the EF-14 trial, extending median overall survival from 16 to 20.9 months in the TTF arm. TTF works by disrupting GBM cell division through low-intensity alternating electric fields applied via scalp transducers. It is an incremental but real advance — yet even with TTF, the five-year survival rate remains below five percent.
Current Modalities at a Glance
| Modality | Role | Limitation |
|---|---|---|
| Surgery | Cytoreduction; tissue diagnosis; reduces ICP | Incomplete resection nearly universal; infiltrative margins persist |
| Radiotherapy (60 Gy) | Local tumor control post-resection | Cannot safely cover all infiltrative disease; radiation necrosis risk |
| Temozolomide | DNA alkylation; benefit greatest in MGMT-methylated tumors | Resistance develops rapidly; limited CNS penetration in some patients |
| Tumor Treating Fields (TTF) | Disrupts GBM cell division via alternating electric fields (200 kHz) | Device compliance burdensome; ~4 month median OS benefit |
The Surgical Frontier: Pushing the Limits of Resection
The cornerstone of the Stupp protocol is surgery, and the central surgical imperative is straightforward: remove as much tumor as safely possible. Extent of resection (EOR) is one of the most consistently identified prognostic factors in GBM. Gross total resection (GTR) of the contrast-enhancing tumor — the visible, vascularized core — is associated with improved progression-free and overall survival compared to subtotal resection.
Achieving GTR in GBM is, however, technically demanding. The tumor's infiltrative biology means that neoplastic cells extend well beyond radiographic margins into surrounding functional brain tissue. Neurosurgeons must navigate a fundamental tension: aggressive resection risks permanent neurological deficit, while conservative resection leaves behind microscopic disease that drives early recurrence. Over the past two decades, a suite of intraoperative adjunct technologies has been developed to address this tension.
Surgical Adjuncts: The State of the Art
Three technologies have substantially reshaped the modern GBM operating room: awake craniotomy with cortical and subcortical mapping, intraoperative MRI, and 5-ALA fluorescence-guided surgery. Each addresses a distinct dimension of the same underlying challenge — maximizing extent of resection while preserving neurological function.
Awake Craniotomy with Cortical & Subcortical Mapping
When a GBM lies within or adjacent to eloquent cortex — the language, motor, or sensory regions where damage would be catastrophic for quality of life — extent of resection can be significantly limited. Awake craniotomy (AC) is performed while the patient is conscious and responsive. Intraoperative neurological monitoring with real-time cortical and subcortical stimulation mapping helps define the intersection of eloquent brain tissue and tumor.
The evidence supporting AC is well established: the GLIOMAP study — a large propensity-matched multinational cohort — found that awake craniotomy reduced neurological deficits while enabling more aggressive resection in GBM patients with eloquent-area tumors, largely irrespective of age or preoperative functional status. A single-institution retrospective analysis of left hemispheric eloquent GBM found that patients undergoing AC demonstrated better postoperative functional scores, and longer progression-free and overall survival, compared to surgery under general anesthesia.
AC is not universally applicable — it requires patient tolerance, appropriate tumor location, and institutional expertise — but in the right setting, it represents the most direct tool available for reconciling maximal resection with neurological preservation.
Permanent neurological deficit: ~5% (AC) vs. ~20% (asleep) in eloquent GBM cohortsIntraoperative MRI (iMRI)
Even an experienced surgeon working with real-time neuronavigation can be misled by brain shift — the displacement of brain tissue that occurs as CSF drains and resection proceeds. Preoperative MRI coordinates become progressively less accurate as the operation continues, leading surgeons to underestimate residual tumor. Intraoperative MRI corrects for this by acquiring updated imaging mid-procedure.
High-field iMRI suites (1.5T or 3T) allow surgeons to pause resection, image the operative field, identify residual enhancing tumor, and return to the table to pursue additional resection. In a randomized controlled trial of iMRI guidance versus conventional neuronavigation for high-grade glioma, iMRI led to significantly higher rates of complete resection of contrast-enhancing tumor. The technology also serves a quality-assurance function: confirming adequacy of resection before the patient leaves the operating room.
↑ Complete contrast-enhancing tumor resection rates with iMRI vs. conventional neuronavigation (RCT evidence)5-ALA Fluorescence-Guided Surgery (FGS)
5-aminolevulinic acid (5-ALA) fluorescence-guided surgery is the most widely adopted intraoperative visualization adjunct in GBM surgery, and the only fluorophore with established regulatory approval and robust clinical evidence in this setting. Administered orally several hours before surgery, 5-ALA is selectively taken up and metabolized by high-grade glioma cells, producing a fluorescent porphyrin — protoporphyrin IX (PpIX) — detectable under blue-violet light in the operating microscope, enabling real-time intraoperative tumor visualization.
The mechanism depends on three factors unique to GBM cells: disruption of the blood-brain barrier allowing 5-ALA penetration, upregulated porphyrin metabolism in tumor cells, and dysfunction of ferrochelatase — the enzyme that would otherwise convert PpIX into non-fluorescent heme in normal brain cells.
A landmark comparison found that introducing 5-ALA FGS improved the mean volumetric extent of resection of T1-enhancing lesions from 84.7% to 97.0%, and raised complete resection rates from 43% to 80%. Importantly, 5-ALA FGS has demonstrated effectiveness even in recurrent GBM settings, with a positive predictive value exceeding 99%. Next-generation near-infrared fluorophores and quantitative spectroscopy tools are under active investigation to address remaining depth-resolution constraints.
GTR rate: 80% (5-ALA) vs. 43% (white light) in single-surgeon comparative seriesThe Persistent Biological Challenge
The surgical adjuncts described above represent meaningful clinical advances. Awake craniotomy reduces rates of permanent neurological deficit in eloquent-area resections. Intraoperative MRI corrects for brain shift and enables confirmation of resection adequacy. 5-ALA FGS substantially increases gross total resection rates and provides real-time tumor delineation. Together, these technologies have materially improved the proportion of patients achieving complete resection of contrast-enhancing disease.
Nevertheless, they share a common limitation. Each addresses the contrast-enhancing, blood-brain-barrier-disrupting core of the tumor — the component of GBM that is, by definition, most visible. None adequately addresses the infiltrative glioblastoma stem cell (GSC) population that has already disseminated into surrounding brain parenchyma, resides behind an intact blood-brain barrier, and is invisible to the imaging and fluorescent signals that guide resection. This GSC population is widely understood to be the principal driver of local recurrence, accounting for the greater-than-80% rate of relapse within two centimeters of the resection margin.
This protected status of infiltrating GBM cells defines the therapeutic rationale for our program. UP Oncolytics is developing wild-type Zika virus (ZIKV) strains that can target GBM cells behind the blood-brain barrier. ZIKV's selective tropism for GSCs is mediated through AXL and integrin αvβ5 receptors that are overexpressed by GBM stem cells, conferring a degree of tumor-cell specificity that cannot be replicated by surgery, radiation, or traditional chemotherapy. Our approach is designed to complement the surgical and adjuvant therapies described above by addressing the residual disease they cannot reach.
Addressing Residual Disease: The Case for Oncolytic Virotherapy
Surgery, radiotherapy, temozolomide, and TTF will remain the foundation of GBM management for the foreseeable future. The intraoperative adjuncts reviewed here have advanced surgical practice, and the field continues to evolve with next-generation fluorophores, quantitative Raman spectroscopy, and refined diffusion tensor imaging for white matter tract preservation.
However, no surgical instrument — however precisely guided — can pursue individual tumor cells that have migrated into functional brain parenchyma. Addressing this residual disease requires a fundamentally different class of therapeutic: one capable of penetrating an intact blood-brain barrier, identifying GSCs by their surface receptor profile, and selectively eliminating them without injury to surrounding normal neural tissue.
In subsequent posts, we will describe in detail how wild-type ZIKV strains fulfil this biological brief — and why their natural properties, rather than any engineering intervention, are central to their therapeutic potential.