Leveraging Metalloinsertors for the PET Imaging and Endoradiotherapy of MMR-Deficient Cancers

利用金属插入器对 MMR 缺陷癌症进行 PET 成像和腔内放射治疗

基本信息

批准号：
10686864
负责人：
Samantha Patricia Delaney
金额：
$ 3.32万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686864
关键词：
Adenine Affinity Base Pair Mismatch Base Pairing Binding Biodistribution Biological Cell Proliferation Cells Chemicals Clinical Management Colorectal Cancer Complex Critical Pathways Cytosine DNA DNA Binding DNA Minor Groove Binding DNA Repair DNA Repair Pathway Data Development Diagnostic Eukaryotic Cell Evaluation Exhibits Exposure to Family Family member Generations Genome Genomic DNA Halogens Hand Hereditary Nonpolyposis Colorectal Neoplasms High Pressure Liquid Chromatography Human I131 isotope In Vitro Investigation Iodine Iodine Radioisotopes Label Ligands Major Groove Malignant Neoplasms Mismatch Repair Mismatch Repair Deficiency Mus Mutation Nucleotides Patient-Focused Outcomes Patients Performance Phenanthrolines Play Polymerase Positron Positron-Emission Tomography Prognosis Protein Family Radiation therapy Radio Radiolabeled Radiopharmaceuticals Rhodium Role Single Nucleotide Polymorphism Site Solid Neoplasm Specificity Syndrome Technology Thermodynamics Thin Layer Chromatography Toxic effect Validation Variant Wit Work Xenograft procedure analog base cancer cell cellular development chemical synthesis colon cancer cell line dosimetry experimental study gene repair genome integrity genotoxicity imaging agent improved in vivo in vivo evaluation innovation mouse model novel nuclear imaging radiotracer scaffold subcutaneous theranostics therapeutic target tool tumor tumor behavior tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY / ABSTRACT DNA repair pathways are critical for maintaining the integrity of the genome. Yet polymerase errors and exposure to genotoxic chemicals may lead to the dysregulation of the mismatch repair (MMR) machinery, the family of proteins responsible for identifying and correcting mispaired bases in genomic DNA. When this machinery malfunctions - or is absent altogether - single base mismatches can accumulate, making cells prone to the generation of single nucleotide polymorphisms (SNPs) and, eventually, tumorigenesis. Indeed, up to 20% of all solid tumors have been shown to be MMR-deficient. Most notably, MMR-deficiency plays a significant role in the development of hereditary nonpolyposis colorectal cancer (HNPCC). The last twenty years have witnessed the development of octahedral rhodium complexes that selectively and specifically bind DNA mismatches. These compounds, known as ‘metalloinsertors’, have been shown to exhibit preferential anti- proliferative effects in vitro in MMR-deficient vs. MMR-proficient colorectal cancer cells and to inhibit tumor growth in vivo in a murine model of colorectal cancer. This F31 proposal is focused on the synthesis, in vitro evaluation, and in vivo validation of a novel family of radiopharmaceuticals based on the mismatch-targeting metalloinsertor RhPBC. We first plan to synthesize non- radioactive natI-RhPBC to facilitate the chemical and biological characterization of the probe. Subsequently, we will create analogues of the metalloinsertor labeled with radioisotopes of iodine - either positron-emitting iodine- 124 (124I; t1/2 ~ 4.2 d) or ß-emitting iodine-131 (131I; t1/2 ~ 8.0 d) - to create radiopharmaceuticals for PET imaging and endoradiotherapy, respectively. Specific Aim 1 will be focused on the chemical synthesis and analysis of all three compounds (natI-RhPBC, 124I-RhPBC, and 131I-RhPBC) as well as the biological characterization and in vitro evaluation of the compounds in a pair of isogenic human colorectal cancer cell lines that are identical except for their MMR-proficiency (HCT116N) or MMR-deficiency (HCT116O). In Specific Aim 2, PET imaging and biodistribution experiments will be used to evaluate the in vivo performance of 124I-RhPBC as a diagnostic and theranostic imaging agent in a murine model MMR-deficient colorectal cancer. And finally, Specific Aim 3 will be centered on the in vivo evaluation of 131I-RhPBC as a radiotherapeutic using biodistribution studies, dosimetry calculations, and longitudinal therapy studies in a murine models of MMR-deficient colorectal cancer. We contend that this project is both highly innovative and highly impactful. To the best of our knowledge, DNA mismatches have never before been a target for nuclear imaging and therapy, and octahedral rhodium complexes have not been harnessed as scaffolds for radiotracers. In the short term, this work could produce an imaging agent that could be a useful tool in the clinical management of patients with MMR-deficient tumors. In the longer term, this investigation could also yield a first-in-class radiotherapeutic that could be used against a variety of MMR-deficient tumors, improving prognoses and outcomes for patients with these malignancies.

项目摘要 /摘要 DNA修复途径对于维持基因组的完整性至关重要。但是聚合酶错误和暴露于遗传毒性化学物质可能导致不匹配修复（MMR）机械的失调，即蛋白质家族负责识别和纠正基因组DNA中的错误碱基。当这个机械故障 - 或完全不存在 - 单个基础不匹配可以积累，使细胞容易产生单核苷酸多态性（SNP），最终是肿瘤发生。确实，起来所有实体瘤中的20％已被证明是MMR缺陷。最值得注意的是，MMR缺乏效率扮演在遗传非跨性质结直肠癌（HNPCC）的发展中的重要作用。最近二十年见证了八面体阳极铬化物的发展，这些复合物有选择地，特异性地结合DNA 不匹配。这些化合物被称为“金属毒素”，已显示出优先的抗抗在MMR缺陷型与MMR良好的结直肠癌细胞中的体外增殖作用，并抑制肿瘤在大肠癌的鼠模型中，体内生长。该F31提案的重点是综合，体外评估和体内验证的新型家族放射性药物基于不匹配的金属素体RHPBC。我们首先计划合成非 - 放射性NATI-RHPBC促进探针的化学和生物学表征。随后，我们将创建用碘的放射性异位素标记的金属素的类似物 - 要么将正电子发射碘 - 124（124i; t1/2〜4.2 d）或ß发射碘131（131i; t1/2〜8.0 d） - 创建用于宠物成像的放射性药物和内二疗法。具体目标1将集中于化学合成和分析所有三种化合物（NATI-RHPBC，124i-RHPBC和131i-RHPBC）以及生物学表征和在在一对同基因的人结直肠癌细胞系中对化合物的体外评估，除了对于他们的MMR生产能力（HCT116N）或MMR缺乏（HCT116O）。在特定目标2中，宠物成像和生物分布实验将用于评估124i-RHPBC的体内性能作为诊断和鼠模型MMR缺陷结直肠癌中的疗法成像剂。最后，特定的目标3将使用生物分布研究，剂量测定法以131i-RHPBC作为放射治疗的体内评估为中心计算和纵向治疗研究MMR缺陷结直肠癌模型。我们认为该项目既具有创新性，又具有很高的影响力。据我们所知， DNA不匹配从来没有成为核成像和治疗的靶标，而八面体若im 复合物尚未作为放射性示例的脚手架。在短期内，这项工作可能会产生成像剂可能是MMR缺陷肿瘤患者的临床管理中有用的工具。在从长远来看，这项投资还可以产生一流的放射线治疗，可以用来与A 多种MMR缺陷肿瘤，改善了这些恶性肿瘤患者的预后和预后。