Targeting DNA Mismatches for Auger Electron Radiotherapy

针对 DNA 错配进行俄歇电子放射治疗

• 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
• 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

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.

项目摘要/摘要 DNA碱基对不匹配可能是由于聚合酶错误或接触到遗传毒性化学物质造成的。而当 真核细胞已经进化出一种复杂的错配修复(MMR)机制来防范这些 事件，具有失活MMR系统的细胞通过胚系突变、体细胞突变、启动子 超甲基化或其某种组合不能修复这些错误，导致积累 突变和增加肿瘤发生的可能性。也就是说，15%的结直肠癌和95%的 遗传性非息肉病结直肠癌是错配修复缺陷。然而，尽管它在结直肠癌中无处不在 癌症和其他恶性肿瘤和临床迫切需要新的靶向治疗方法，MMR缺乏症 仍然是一个未得到充分利用的治疗靶点。过去的20年见证了一个家庭的发展 被称为“金属插入物”的八面体Rh络合物能高选择性地结合DNA错配和 亲和力。金属插入物从小凹槽接近DNA并通过破坏DNA结合到错配的位置 热力学上不稳定的碱基对，将错配的核苷酸喷射到主槽中，以及 用它们的空间膨胀配体取代p-堆叠中排出的碱基。 这份R21提案的重点是利用这种金属插入器技术来创造一种新的不匹配- 靶向放射治疗。为此，我们将转向俄歇电子发射放射性核素 碘-123(123I；T1/2~13小时)≈，因为它能够在非常小的半径内储存大量能量 在腐烂的地方周围。我们认为，将错配选择性金属插入物与核素相结合 在如此短的范围内施加辐射毒性将产生一种具有前所未有的选择性的治疗方法。自.以来 金属络合物只结合不匹配的DNA，它只会将放射性核素传递到离DNA足够近的地方 通过MMR缺陷细胞内的俄歇电子级联产生焦点高LET损伤。具体目标1将 重点研究了一种放射性碘错配选择性化合物的合成和化学表征 金属插入物~(123)I-RhIPC~(3+)及其在一对同基因人体内的放射生物学研究 MMR熟练和MMR缺陷的人结直肠癌细胞系。具体目标2将集中在 ~(123)I-RhIPC在原位MMR阳性和MMR阴性小鼠体内的实验研究 通过生物分布实验、剂量学计算和纵向研究发现缺陷性结直肠癌异种移植 治疗研究。 最终，提议的项目承诺开发和验证一类全新的 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治疗 这可以用于MMR缺陷的结直肠癌患者。从长远来看，这项调查可能 开创了一个利用金属插入物进行核成像和靶向放射治疗的时代 广泛的MMR缺陷癌症。