# Maximizing Local Access to Therapeutic Deliveries in Glioblastoma

> **NIH NIH P01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $1,827,419

## Abstract

Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. The major obstacles to GBM
treatment are the accessibility of GBM tumors to drugs through natural physiological and pathobiological
barriers like the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively, and the
adequate properties of drugs. In addition, complex pathobiology of GBM, including local invasion and
intratumoral heterogeneity represent major challenges to generating effective anti-GBM drugs. The unifying
theme of our PPG is the exploitation of local access to brain tumors like GBM to achieve and then maximize
therapeutic effect in patients. This local access can be accomplished either by direct loco-regional delivery of
drugs into the tumor mass and its vicinity or by disrupting the BBB/BBTB. For example, drugs can be delivered
locally through convection-enhanced delivery (CED). The overall hypothesis of this PPG is that we can deliver
the next generation of molecularly targeted drug candidates to GBM effectively by either significantly re-
designed CED and/or by precision BBB/BBTB disruption. To address this hypothesis, we are developing
convection-enhanced thermo-chemotherapy catheter system (CETCS) based on a novel arborizing catheter.
Furthermore, the BBB disruption will be tested in two innovative ways using: (i) high-frequency irreversible
electroporation (H-FIRE), or (ii) a combined approach of stem cells expressing tumor necrosis factor-α (TNF),
a cytokine with a potential to significantly enhance BBB permeability, under a heat responsive promoter that
can be remotely activated using high intensity focused ultrasound (HIFU). We will exploit a unique animal
model of spontaneous gliomas in dogs, which is amenable to testing medical devices/surgical procedures, and
thus is one of the most valuable tools in addressing our PPG's unifying theme. We will explore our hypothesis
in three Specific Aims. In Aim 1, we will generate targeted cytotoxic drugs with an increased access to tumors
and/or pathophysiologically important tumor compartments. We will generate targeted drug conjugates with
BBB-penetrating chemotherapeutics. In Aim2, we will attempt to bypass the BBB/BBTB by developing CED
that addresses critical clinical needs. We will evaluate an arborizing catheter for broad distribution of infusates
and accurate saturation of target volume in brain tissue. We will evaluate targeted drugs distribution and
efficacy by CETCS for treating spontaneous GBM in a canine model. In Aim 3, we will bypass the BBB/BBTB
by induced disruption. This will be achieved with H-FIRE treatment allowing for preferential targeting infiltrating
tumor cells. We will assess H-FIRE protocols to combinatorially treat spontaneous gliomas in dogs with
targeted cytotoxic agents. We will also examine stem cells engineered to express TNFα. Thus, our PPG
proposal represents a combined rational approach of novel therapeutic approaches to improve delivery of
unique drug ...

## Key facts

- **NIH application ID:** 10220880
- **Project number:** 5P01CA207206-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Waldemar Debinski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,827,419
- **Award type:** 5
- **Project period:** 2017-08-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220880

## Citation

> US National Institutes of Health, RePORTER application 10220880, Maximizing Local Access to Therapeutic Deliveries in Glioblastoma (5P01CA207206-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10220880. Licensed CC0.

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