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Principal Investigator: Scott R Floyd
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $413,971
Funding agency: National Cancer Institute
ABSTRACT: Radiation therapy is a necessary component of current treatment for many brain tumors.
Radiation therapy leverages a therapeutic ratio in which tumor cells suffer radiation damage and die, while
normal brain cells repair radiation damage and are less negatively affected. Improvements in the therapeutic
ratio are badly needed both to improve brain tumor cure probability and limit risk for radiation effects on the
normal brain such as radiation necrosis and neurocognitive dysfunction. Efforts to widen the therapeutic
window for radiation therapy of brain tumors have included chemical approaches to combine RT with drugs
intended to increase tumor cell radiosensitivity, or normal cell radioresistance, however, to date, few effective
therapies have emerged. Recently, advances in physics have produced “ultra-high” rates of radiation dose
delivery (termed “FLASH-RT”). Compelling reports point to normal tissue protection with FLASH-RT dose
delivery, however the molecular mechanism of FLASH-RT is largely unknown. Interestingly, ferroptosis cell
death mechanisms have been implicated. Our multidisciplinary collaborative team has leveraged
complementary expertise to develop resources and preliminary data to improve the brain tumor radiation
therapy therapeutic window through both chemical and physical means. We have created a unique
experimental platform with two novel components: 1) A highly tunable, very high dose-rate electron FLASH-
RT beam provided by the High Intensity Gamma-ray Source (HIGS) at the Triangle Universities Nuclear
Laboratory (TUNL) and 2) an Organotypic brain slice culture (OBSC) assay platform that allows interrogation of
both tumor and normal brain tissue cells in an elevated-throughput dry-culture system highly amenable to
experiments with both standard RT and our unique FLASH-RT beam. Encouragingly, preliminary data in our
OBSC system shows that ATM kinase inhibition seems to protect neurons from ferroptotic death. To achieve
our long-term goal to widen the therapeutic window, we propose two hypotheses: 1) ATM inhibition can widen
the radiation therapeutic window for brain tumors by sensitizing tumor cells and protecting neurons especially
under FLASH-RT conditions, and 2) Cancer cells depend on adaptations to maintain rapid growth in the brain,
and these adaptations can be exploited to enhance tumor cell killing. We will test these hypotheses with the
following aims: 1) Optimize HIGS-FLASH beam parameters (dose, dose-rate, targeting) for enhanced
metastatic brain tumor cell kill with maximal protection of normal brain under normal and ATM inhibition
conditions. 2) Test genetic targets for radiation sensitization in glioblastoma cells under standard and FLASH-
RT dose rates in the OSBC system. We expect that this project will elucidate cytotoxic mechanisms of both
standard and FLASH-RT and generate highly-translatable drugs and drug targets to widen the therapeutic
window for brain tumors. If successful, this project will expand to larger screening sets and additional brain
tumor types, with in vivo model validation.
Terms: <ATM Protein><ATM Serine/Threonine Protein Kinase><ATM gene><ATM kinase><ATM protein kinase><Address><Affect><Animal Experiments><Assay><Ataxia Telangiectasia Mutated><Ataxia Telangiectasia Protein><Ataxia-Telangiectasia Gene><Ataxia-Telangiectasia Mutated Gene><Ataxia-Telangiectasia-Mutated protein kinase><Behavioral><Bioassay><Biochemical><Biological Assay><Brain><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CNS Tumor><CNS neoplasm><CRISPR><CRISPR/Cas system><Cell Body><Cell Death><Cells><Central Nervous System Neoplasms><Central Nervous System Tumors><Cessation of life><Chemicals><Clustered Regularly Interspaced Short Palindromic Repeats><Combination Drug Therapy><Combined Modality Therapy><Coupling><Custom><DNA Damage><DNA Injury><Data><Death><Dependence><Dose><Dose Rate><Drug Combinations><Drug Screening><Drug Targeting><Drugs><Dryness><Dysfunction><Electrons><Encephalon><Experimental Neoplasms><Experimental Tumor><Functional disorder><Gamma Radiation><Gamma Rays><Genes><Genetic Screening><Glioblastoma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Histology><Human><IQ Deficit><Investigation><Knock-out><Knockout><L-Serine><Laboratories><Libraries><Louis-Bar Syndrome Gene><Malignant Cell><Medical><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monitor><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Negative Beta Particle><Negatrons><Nerve Cells><Nerve Unit><Neural Cell><Neurocognitive><Neurocognitive Deficit><Neurocyte><Neurons><Normal Cell><Normal Tissue><Normal tissue morphology><Nuclear><Outcome><Pathway interactions><Pharmaceutical Preparations><Physics><Physiopathology><Polychemotherapy><Probability><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><Publishing><Radiation><Radiation Biology><Radiation Dose><Radiation Dose Unit><Radiation Oncologist><Radiation Sensitivity><Radiation Tolerance><Radiation induced damage><Radiation necrosis><Radiation therapy><Radiobiology><Radioresistance><Radiosensitivity><Radiosensitization><Radiotherapeutics><Radiotherapy><Reporting><Research Resources><Resources><Role><Serine><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Slice><Source><System><Testing><Therapeutic><Threonine Kinase><Toxic effect><Toxicities><Tumor Cell><Tumor Tissue><Universities><Validation><Work><animal experiment><ataxia telangiectasia mutated protein><beamline><brain cell><brain tissue><cancer cell><cell killing><chemo-/radio-sensitization><clinical relevance><clinically relevant><combination chemotherapy><combination pharmacotherapy><combination therapy><combined modality treatment><combined treatment><conventional dosage><conventional dosing><customs><cytotoxic><drug/agent><effective therapy><effective treatment><electron energy><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><gene testing><gene-based testing><genetic approach><genetic strategy><genetic testing><glioblastoma multiforme><high energy physics><improved><in vivo><in vivo Model><intelligence quotient deficit><irradiation response><multi-modal therapy><multi-modal treatment><multidisciplinary><necrocytosis><neoplastic cell><neurocognitive decline><neurocognitive impairment><neuronal><neuroprotection><neuroprotective><novel><pathophysiology><pathway><radiation damage><radiation effect><radiation resistance><radiation response><radiation risk><radiation sensitization><radiation treatment><radio resistance><radio-/chemo-sensitization><radio-sensitivity><radio-sensitization><radiosensitive><radiotherapy sensitization><rapid growth><repair><repaired><response><response to radiation><screening><screenings><side effect><social role><spongioblastoma multiforme><success><therapy optimization><traditional dosage><traditional dosing><treatment optimization><treatment with radiation><tumor><tumors in the brain><tumors in the central nervous system><validations><γ-Radiation><γ-Ray>