R21NS126810

Cysteine depletion-induced ferroptosis as a therapeutic vulnerability in glioblastoma is the most malignant and commonly diagnosed primary brain tumor in adults with a dismal median overall survival of 14 to 16 months. In 2005, the Stupp regimen changed clinical care with the discovery that the chemotherapeutic drug temozolomide (TMZ), with the addition of surgery and radiation, could extend patient survival. However, new therapeutic avenues have remained stagnant and with no second-line therapeutic options showing significant improvement in recurrent GBM tumors, resistance to TMZ is uniformly fatal.

To this end, we sought to better understand the molecular mechanisms of TMZ-resistant disease to provide patients a potential second-line therapeutic option with a focus on cysteine depletion-induced ferroptosis in TMZ-resistant GBM. Ferroptosis is an iron-dependent form of cell death which has recently gained attention as an attractive avenue to eradicate otherwise drug resistant cancer cells.

Our preliminary data support the role of a previously uncharacterized metabolic enzyme in the induction of cysteine depletion-induced ferroptosis. Our findings strongly suggest that the gamma ()-glutamyl enzyme (-glutamylcyclotransferase; GGCT) recycles cysteine and prevents glutathione (GSH) production – the main goal of the -glutamyl pathway. We further show that TMZ-resistant cells have changes consistent with a sensitivity to ferroptosis induction such as an increase in reactive oxygen species (ROS), cysteine uptake, and the cysteine/glutamate antiporter – XCT, as well as mislocalized perinuclear mitochondria.

Therefore, we sought to repurpose ebselen, a previously characterized neuroprotective agent that was thought to be a glutathione peroxidase 4 (GPX4) mimetic but has recently garnered attention for its selenium ion's ability to covalently bind cysteines. We show that the neuroprotective agent ebselen, which has already been shown to cross the blood-brain barrier – a major hurdle for GBM treatment – specifically targets TMZ-resistant GBM cells in vitro.

Based on these results, we propose to further investigate the role of cysteine recycling via GGCT and its therapeutic potential as a treatment vulnerability in patient-derived xenograft (PDX) TMZ-resistant GBM orthotopic pre-clinical animal models. Lastly, we seek to establish prognostic biomarkers of this aberrant cysteine recycling through a metabolic byproduct of GGCT's enzymatic activity in clinical glioma specimens.

Overall, this proposal will give insight into a new avenue of ferroptosis induction in drug-resistant GBM and potentially pave the way for cysteine deprivation-induced ferroptosis in other drug-resistant cancers.

Northwestern University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (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. TO UTILIZE THE 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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Illinois United States

State-Wide

Joint NINDS/NIMH Exploratory Neuroscience Research Grant (R21 Clinical Trial Optional) (PA-21-219)

Amendment Since initial award the End Date has been extended from 04/30/24 to 04/30/26 and the total obligations have increased 83% from $240,000 to $440,000.