Targeting DNA Mismatches for Auger Electron Radiotherapy
针对 DNA 错配进行俄歇电子放射治疗
基本信息
- 批准号:10751210
- 负责人:
- 金额:$ 45.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-08 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAdenineAffinityAllelesBase Pair MismatchBase PairingBehaviorBindingBiodistributionCell NucleusCell ProliferationCellsChemicalsClinicalColorectal CancerComplexCytosineCytosolDNADNA BindingDNA DamageDNA Minor Groove BindingDNA RepairDataDepositionDevelopmentDiscipline of Nuclear MedicineElectronsEukaryotic CellEvaluationEventExhibitsExposure toExtracellular SpaceFamilyFamily memberGenesGenomeGerm-Line MutationHandHereditary Nonpolyposis Colorectal NeoplasmsHumanHypermethylationIn VitroInvestigationIodineIodine IsotopesLabelLigandsLinear Energy TransferLoss of HeterozygosityMLH1 geneMSH2 geneMSH3 geneMSH6 geneMajor GrooveMalignant NeoplasmsMismatch RepairMismatch Repair DeficiencyMusMutationNuclear MatrixNucleotidesOrganPMS1 genePMS2 genePatient-Focused OutcomesPatientsPerformancePhenanthrolinesPlayPolymerasePrognosisRadialRadiation ToxicityRadiation therapyRadiobiologyRadioisotopesRadiolabeledRadionuclide therapyRadiopharmaceuticalsResearch DesignRhodiumSingle Nucleotide PolymorphismSiteSolid NeoplasmSomatic MutationSpecificitySystemTargeted RadiotherapyTechnologyTherapeuticThermodynamicsTissuesToxic effectTreatment EfficacyTreatment-related toxicityValidationVariantWitXenograft ModelXenograft procedurebasecancer cellcellular developmentcolon cancer cell linecytotoxicitydosimetryexperimental studygenotoxicityimprovedin vitro testingin vivoin vivo evaluationinnovationmetal complexmouse modelnew therapeutic targetnovelnuclear imagingpromoterradiochemicalrepairedtargeted agenttargeted radiotherapeutictherapeutic targettooltumortumor behaviortumorigenesisuptake
项目摘要
Project Summary/Abstract
Mismatched DNA base pairs can arise due to polymerase errors or exposure to genotoxic chemicals. While
eukaryotic cells have evolved a sophisticated mismatch-repair (MMR) machinery to guard against these
events, cells with inactivated MMR systems ¾ either via germline mutations, somatic mutations, promoter
hypermethylation, or some combination thereof ¾ cannot repair these errors, leading to the accumulation of
mutations and increasing the potential for tumorigenesis. To wit, 15% of colorectal cancers and 95% of
hereditary non-polyposis colorectal cancers are mismatch-repair deficient. Yet despite its ubiquity in colorectal
cancer and other malignancies and the urgent clinical need for new targeted therapeutics, MMR deficiency
remains an underutilized therapeutic target. The last 20 years have witnessed the development of a family of
octahedral rhodium complexes called “metalloinsertors” that bind DNA mismatches with high selectivity and
affinity. Metalloinsertors approach DNA from the minor groove and bind to mismatched sites by disrupting the
thermodynamically destabilized base pair, ejecting the mispaired nucleotides into the major groove, and
replacing the ejected bases in the p-stack with their sterically expansive ligand.
This R21 proposal is focused on leveraging this metalloinsertor technology to create a novel mismatch-
targeted radiotherapeutic. To this end, we will turn to an Auger electron-emitting radionuclide ¾ specifically
iodine-123 (123I; t1/2 ~ 13 h) ¾ due to its ability to deposit large amounts of energy within a very small radius
around the site of decay. We contend that combining a mismatch-selective metalloinsertor with a nuclide that
exerts radiotoxicity over such a short range will produce a therapeutic with unprecedented selectivity. Since the
metal complex only binds mismatched DNA, it will only deliver the radionuclide close enough to the DNA to
produce focal high LET damage via the Auger electron cascade within MMR-deficient cells. Specific Aim 1 will
be focused on the synthesis and chemical characterization of a radioiodinated mismatch-selective
metalloinsertor ¾ dubbed 123I-RhIPC ¾ and the in vitro interrogation of its radiobiology in a pair of isogenic
MMR-proficient and MMR-deficient human colorectal cancer cell lines. Specific Aim 2 will be centered on the
evaluation of the in vivo performance of 123I-RhIPC in mice bearing orthotopic MMR-proficient and MMR-
deficient colorectal cancer xenografts via biodistribution experiments, dosimetry calculations, and longitudinal
therapy studies.
Ultimately, the proposed project promises the development and validation of a completely new class of
radiopharmaceuticals. In the short term, this investigation could produce a safe and effective radiotherapeutic
that could be used in patients with MMR-deficient colorectal cancer. In the longer term, this investigation could
usher in an era in which metalloinsertors are harnessed for the nuclear imaging and targeted radiotherapy of a
wide array of MMR-deficient cancers.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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JOHN L HUMM其他文献
JOHN L HUMM的其他文献
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{{ truncateString('JOHN L HUMM', 18)}}的其他基金
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124I-NaI PET: Building block for precision medicine in metastatic thyroid cancer
124I-NaI PET:转移性甲状腺癌精准医疗的基石
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124I-NaI PET: Building block for precision medicine in metastatic thyroid cancer
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定量成像:生物统计学和医学物理
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8555299 - 财政年份:2000
- 资助金额:
$ 45.76万 - 项目类别:
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