# Pre-Clinical Novel Radiosensitizer Evaluation Program for Brain Tumors

> **NIH NIH U01** · MAYO CLINIC ROCHESTER · 2021 · $593,139

## Abstract

PROJECT SUMMARY
Essentially no progress has been made in the past decade in developing more effective therapies for
glioblastoma (GBM). Despite aggressive treatment with surgery, radiation and temozolomide, the median
survival for GBM remains just over one year. While clinical studies have delineated the important cyto-
reductive effects of radiation, the predominant failure pattern remains within the irradiated tumor volume. The
significant morbidity associated with local progression of GBM represents a pressing unmet medical need. This
project will evaluate 5 novel radio/chemo-sensitizing drugs in GBM patient-derived xenograft (PDX) models
and will develop a rational framework for identifying the most promising combinations that should be taken
forward into clinical testing. This framework can be divided into three sets of Aims:
Aim 1: Define the spectrum of response and potential predictive biomarkers for effective sensitizers.
The radio-sensitizing effects of CTEP agents will be evaluated in vitro and in vivo across an extensive panel of
GBM PDX models. In combination with known mechanisms of action and pharmacodynamic measures of
response identified in these studies, potential mechanistic biomarkers of response will be evaluated in
subsequent in vivo studies. Ultimately, the studies in this aim will provide both an understanding of the fraction
of tumors likely to respond to a specific therapy and may identify potential biomarkers that could be used to
enrich a clinical trial population most likely to benefit from a specific combination strategy.
Aim 2: Correlate key pharmacokinetic and pharmacodynamic markers with drug efficacy.
A comprehensive understanding of drug distribution into tumor and normal tissues, and associated
pharmacodynamic effects, are critical for defining which drugs to move forward into Phase I dose-seeking
studies and to interpret Phase 0 surgical sampling studies. The focus of this aim is to define key parameters,
such as the determinants of free- and bound-drug exposure in plasma, normal brain and brain tumor, and to
relate these metrics to a dose range associated with effective radiosensitization. These studies will enable
predictions from readily available human pharmacokinetic data in plasma as to whether effective
radiosensitizing drug levels should be achievable in human tumors in the brain.
Aim 3: Evaluate the potential for radio-sensitization of normal brain tissues.
Radiation therapy can cause significant long-term neuro-cognitive defects that dramatically impair patient
quality of life. If a specific radiosensitizer is known to potentiate these adverse effects, then this would critically
inform the safe clinical deployment of this strategy. Thus, studies in this aim will evaluate drug/radiation
interactions with respect to neurogenesis, neuro-inflammation and cognition in mouse models to provide an
understanding of how radiosensitizing drug therapy may influence the therapeutic window for brain irradiation.

## Key facts

- **NIH application ID:** 10144403
- **Project number:** 5U01CA227954-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jann N. Sarkaria
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $593,139
- **Award type:** 5
- **Project period:** 2018-06-14 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144403

## Citation

> US National Institutes of Health, RePORTER application 10144403, Pre-Clinical Novel Radiosensitizer Evaluation Program for Brain Tumors (5U01CA227954-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144403. Licensed CC0.

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