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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：
JOHN L HUMM
金额：
$ 45.76万
依托单位：
HUNTER COLLEGE
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：
https://reporter.nih.gov/project-details/10751210
关键词：
Abbreviations Adenine Affinity Alleles Base Pair Mismatch Base Pairing Behavior Binding Biodistribution Cell Nucleus Cell Proliferation Cells Chemicals Clinical Colorectal Cancer Complex Cytosine Cytosol DNA DNA Binding DNA Damage DNA Minor Groove Binding DNA Repair Data Deposition Development Discipline of Nuclear Medicine Electrons Eukaryotic Cell Evaluation Event Exhibits Exposure to Extracellular Space Family Family member Genes Genome Germ-Line Mutation Hand Hereditary Nonpolyposis Colorectal Neoplasms Human Hypermethylation In Vitro Investigation Iodine Iodine Isotopes Label Ligands Linear Energy Transfer Loss of Heterozygosity MLH1 gene MSH2 gene MSH3 gene MSH6 gene Major Groove Malignant Neoplasms Mismatch Repair Mismatch Repair Deficiency Mus Mutation Nuclear Matrix Nucleotides Organ PMS1 gene PMS2 gene Patient-Focused Outcomes Patients Performance Phenanthrolines Play Polymerase Prognosis Radial Radiation Toxicity Radiation therapy Radiobiology Radioisotopes Radiolabeled Radionuclide therapy Radiopharmaceuticals Research Design Rhodium Single Nucleotide Polymorphism Site Solid Neoplasm Somatic Mutation Specificity System Targeted Radiotherapy Technology Therapeutic Thermodynamics Tissues Toxic effect Treatment Efficacy Treatment-related toxicity Validation Variant Wit Xenograft Model Xenograft procedure base cancer cell cellular development colon cancer cell line cytotoxicity dosimetry experimental study genotoxicity improved in vitro testing in vivo in vivo evaluation innovation metal complex mouse model new therapeutic target novel nuclear imaging promoter radiochemical repaired targeted agent targeted radiotherapeutic therapeutic target tool tumor tumor behavior tumorigenesis uptake

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