U19CA264385

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. Unfortunately, current therapy for GBM is incapacitating and limited by non-specific toxicity. Despite numerous clinical trials, only a few agents have been approved for clinical use, and the tumors addressed in this application remain uniformly lethal.

This Glioblastoma Trials Network (GTN) application aims to 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 the 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. The findings from Project 1 will inform the design of the Phase 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 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 pharmacodynamic (PD) assessments of 6-Thio-DG therapy. It will also provide 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 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, if successfully completed, would lead to initial studies of effectiveness in patients with GBM, potentially adding an important new approach to fight GBM.

Duke University

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Durham, North Carolina 277103022 United States

Single Zip Code

Glioblastoma Therapeutics Network (U19 Clinical Trial Required) (RFA-CA-20-047)

Amendment Since initial award the total obligations have increased 324% from $895,748 to $3,794,691.