6-thio-2'-deoxyguanosine: A Novel Immunogenic Telomerase-Mediated Therapy in Glioblastoma - A Duke and UTSW Collaboration

PROJECT SUMMARY – Overall
Glioblastoma (GBM) is one of the most frequent causes of cancer death in children and young adults and is also
the most common malignant primary brain tumor in adults. Moreover, current therapy is incapacitating and is
limited by non-specific toxicity. Despite hundreds of clinical trials, few agents have been approved for clinical
use, and the tumors addressed in this application remain uniformly lethal. This Glioblastoma Trials Network
(GTN) application will address this problem through a collaborative group of translational physician-scientists at
Duke University and the University of Texas Southwestern Medical Center proposing a novel approach for
treatment of GBM using a telomere-targeting drug, 6-thio-2′-deoxyguanosine (6-thio-dG).
Telomerase is an attractive target for anti-GBM therapy as it is over-expressed in the vast majority of
GBM. Additionally, our pre-clinical data shows that treatment of tumor bearing animals with 6-thio-dG leads to
tumor regression through the dual activity of both DNA damage and innate and adaptive immune responses.
Most recently through our collaborative effort we have already commenced studies in GBM with a developmental
plan ideally suited to the GTN. Project 1 will use a variety of model systems to characterize how 6-thio-dG leads
to tumor regression in GBM examining both DNA damage and innate and adaptive immune responses, and will
inform the design of the 0 trial proposed in Project 2. Project 2 will examine mechanisms of tumor escape to 6-
thio-dG treatment in mouse models of GBM, conduct a phase 0 clinical trial of 6-thio-dG treatment in GBM, and,
informed by Project 1 and the Biomarker, Bioinformatics and Biorepository Core, utilize a number of
screening, stratification and pharmacodynamic biomarkers to guide decision-making. The proposed Biomarker,
Bioinformatics and Biorepository Core will support accurate and robust diagnoses and pharmaco-dynamic
(PD) assessments of 6-thio-dG therapy. It will also provide a number of utilities including sample acquisition and
distribution, statistical leadership and expertise in the design, conduct, analysis and reporting of biomarker
studies. The Core will acquire high-quality primary human samples linked with clinical data in Project 2 and
develop and validate innovative analytical and immune profiling strategies to ensure rigorous experimental
design and conduct is consistent across the Projects. The Administrative Core will provide organizational
leadership, fiscal management administrative support, and will monitor research progress, oversee data
operations, ensure compliance and quality, and facilitate communication and collaboration for both Projects. This
GTN proposal benefits from strong leadership, an established collaboration, and the large and diverse population
of patients with glioblastoma who are seen at Duke and UTSW. The proposed work successfully completed
would lead to initial studies of effectiveness in patients with GBM, potentially adding an important new approach
to fight GBM.

Grant Number: 5U19CA264385-05
NIH Institute/Center: NIH
Principal Investigator: David Ashley