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.

项目摘要/摘要由于聚合酶误差或暴露于遗传毒性化学物质，可能出现不匹配的DNA碱基对。尽管真核细胞已经进化出一种复杂的不匹配修复程序（MMR）机制以防止这些事件，通过种系突变，躯体突变，启动子灭活的MMR系统灭活的细胞¾ 高甲基化或某些组合¾无法修复这些错误，导致积累突变并增加肿瘤发生的潜力。智慧，有15％的结直肠癌和95％遗传性非型结直肠癌是不匹配的治疗方法。目的地的无处不在癌症和其他恶性肿瘤以及新靶向疗法的紧急临床需求MMR缺乏症仍然是未充分利用的治疗靶点。过去20年见证了一个家庭的发展八面体菱形配合物称为“金属毒剂”，其结合DNA不匹配具有高选择性和亲和力。金属词从小凹槽接近DNA，并通过破坏与错位的位点结合热力学不稳定的碱基对，将遗物的核苷酸驱射到主要的凹槽中，然后用其在空间扩展的配体中代替P-stack中的弹出碱。该R21提案的重点是利用这种金属素技术来创造一种新颖的不匹配 - 靶向放射治疗。为此，我们将专门求助于螺旋钻电子发射x x¾ 碘123（123i; t1/2〜13 h）¾由于能够在非常小的半径内沉积大量能量在腐烂的地点周围。我们认为，将错配的属性金属素和一个核素结合在一起在如此短的范围内发挥放射性毒性，将产生具有前所未有的选择性的治疗性。自从金属配合物仅结合不匹配的DNA，它只能将放射性辐射板传递到足够近的DNA到DNA 通过MMR缺陷型细胞内的螺旋钻电子级联反应产生局灶性损害。具体目标1将专注于放射性错调的合成和化学表征金属素体¾被称为123i-rhipc¾和一对等源性的放射性生物学的体外询问富有MMR和MMR的人类结直肠癌细胞系。具体目标2将集中在评估具有原位MMR和MMR-的小鼠中123i-Rhipc的体内性能通过生物分布实验，剂量计算和纵向进行碎片结直肠癌的Xenographictics 治疗研究。最终，拟议的项目承诺开发和验证全新的一类放射性药物。在短期内，这项研究可能会产生安全有效的放射治疗可以用于MMR缺陷型结直肠癌的患者。从长远来看，这项调查可以在一个时代，将金属素的核成像和靶向放射疗法利用广泛的MMR缺陷癌症。