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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/摘要由于聚合酶错误或暴露于遗传毒性化学物质，可能会出现DNA碱基对错配。而真核细胞已经进化出一种复杂的错配修复（MMR）机制来防止这些缺陷。事件中，具有失活MMR系统的细胞通过种系突变、体细胞突变、启动子高甲基化或其某种组合不能修复这些错误，导致高甲基化的积累。突变并增加肿瘤发生的可能性。也就是说，15%的结直肠癌和95%的遗传性非息肉病性结肠直肠癌是错配修复缺陷的。然而，尽管它在结直肠癌中无处不在，癌症和其他恶性肿瘤以及对新靶向治疗的迫切临床需求，MMR缺乏仍然是未充分利用的治疗靶点。在过去的20年里，我们见证了一个家庭的发展。八面体铑络合物，称为“金属插入物”，以高选择性结合DNA错配，亲和力金属插入子从小沟接近DNA，并通过破坏DNA的结合来结合错配位点。 - 使碱基对不稳定，将错配的核苷酸喷射到大沟中，以及用它们的空间扩展配体替换p-堆叠中的排出碱基。这项R21提案的重点是利用这种金属插入物技术来创造一种新的失配- 目标辐射。为此，我们将专门转向俄歇电子发射放射性核素2 H2。碘-123（123 I; t1/2 ~ 13 h）由于其在非常小的半径内存款大量能量的能力在腐烂的地方。我们认为，将错配选择性金属插入剂与在如此短的范围内发挥放射毒性将产生具有前所未有的选择性的治疗剂。以来金属络合物只结合错配的DNA，它只会提供足够接近DNA的放射性核素，通过MMR缺陷细胞内的俄歇电子级联产生局灶性高LET损伤。具体目标1将重点是放射性碘标记的错配选择性的合成和化学表征，被称为123 I-RhIPC的金属插入物123及其在一对等基因的细胞中的放射生物学的体外询问 MMR-proficient和MMR-deficient人结直肠癌细胞系。具体目标2将集中在评价123 I-RhIPC在携带原位MMR-熟练和MMR-的小鼠中的体内性能通过生物分布实验、剂量学计算和纵向研究，治疗研究。最终，拟议的项目承诺开发和验证一种全新的放射性药物在短期内，这项研究可以产生一种安全有效的放射性物质，可以用于MMR缺陷的结直肠癌患者。从长远来看，这项调查可能会开创了一个时代，在这个时代中，金属插入物被用于核成像和靶向放射治疗。多种MMR缺陷型癌症