R37CA258346

Targeting Nucleotide Metabolism to Overcome Therapy Resistance in Glioblastoma - Abstract

Glioblastoma (GBM) is the most common aggressive primary brain tumor and is uniformly fatal with a median survival of around 1.5 years. Like surgery and chemotherapy, radiation (RT) is a critical treatment for nearly every patient with GBM and has repeatedly improved patient survival in multiple randomized trials. Still, 80% of GBMs recur within the high dose RT field. Thus, there is a critical need to develop strategies to overcome GBM RT-resistance to further improve patient outcomes.

GBM cells exhibit profound cancer-specific metabolic abnormalities, including elevated purine synthesis, to fuel proliferation, invasion, and survival. We have found that the metabolic phenotype of elevated purine synthesis also mediates resistance to RT in GBM by promoting the repair of RT-induced DNA damage. This purine-mediated RT resistance can be overcome in preclinical models by mycophenolate mofetil (MMF), an FDA-approved and CNS-penetrant inhibitor of purine synthesis.

In this research proposal, we will determine how the RT response and purine synthesis regulate one another in GBM. We will also determine if the GBMs with the greatest activity of purine synthesis derive the greatest benefit from MMF treatment. Finally, we will perform a clinical trial to determine the maximum tolerated dose of MMF given in combination with RT for patients with GBM and confirm that this dose reaches active concentrations in GBM tissue.

Together, these studies will:
1. Determine mechanistic links between the RT response and purine metabolism in GBM that will facilitate the rational combination of metabolic inhibitors with DNA damage-inducing therapeutics.
2. Determine whether measuring purine synthesis rates could predict GBM response to MMF treatment.
3. Determine whether combined RT and MMF should be evaluated in randomized trials for patients with GBM.

Regents Of The University Of Michigan

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. 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.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Ann Arbor, Michigan 481091276 United States

Single Zip Code

National Cancer Institute's Investigator-Initiated Early Phase Clinical Trials for Cancer Treatment and Diagnosis (R01 Clinical Trials Required) (PAR-18-560)

Amendment Since initial award the total obligations have increased 498% from $554,870 to $3,315,768.