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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：
10537195
负责人：
Samantha Patricia Delaney
金额：
$ 3.22万
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/10537195
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 Lead 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.

项目概要/摘要 DNA 修复途径对于维持基因组的完整性至关重要。然而聚合酶错误和接触基因毒性化学物质可能会导致错配修复（MMR）机制失调，负责识别和纠正基因组 DNA 中错配碱基的蛋白质家族。当这个机器故障 - 或完全不存在 - 单碱基错配会积累，使细胞容易产生单核苷酸多态性（SNP），并最终导致肿瘤发生。确实，上 20% 的实体瘤已被证明存在 MMR 缺陷。最值得注意的是，MMR 缺乏会影响在遗传性非息肉病性结直肠癌（HNPCC）的发展中发挥重要作用。过去二十年见证了选择性、特异性结合 DNA 的八面体铑配合物的发展不匹配。这些被称为“金属插入物”的化合物已被证明具有优先抗- 错配修复缺陷 (MMR) 与错配修复 (MMR) 充分的结直肠癌细胞的体外增殖作用以及抑制肿瘤的作用在结直肠癌小鼠模型中体内生长。该 F31 提案的重点是新家族的合成、体外评估和体内验证基于错配靶向金属插入器 RhPBC 的放射性药物。我们首先计划合成非放射性 natI-RhPBC 有助于探针的化学和生物表征。随后，我们将创建用碘放射性同位素（发射正电子的碘）标记的金属插入器的类似物 124 (124I; t1/2 ~ 4.2 d) 或 ß-发射碘 131 (131I; t1/2 ~ 8.0 d) - 制造用于 PET 成像的放射性药物和腔内放射治疗。具体目标 1 将侧重于化学合成和分析所有三种化合物（natI-RhPBC、124I-RhPBC 和 131I-RhPBC）以及生物学特性和在一对同基因人结直肠癌细胞系中对化合物进行体外评估，除了 MMR 熟练程度 (HCT116N) 或 MMR 缺乏程度 (HCT116O)。在具体目标 2 中，PET 成像和生物分布实验将用于评估 124I-RhPBC 作为诊断和治疗药物的体内性能 MMR 缺陷型结直肠癌小鼠模型中的治疗诊断成像剂。最后，特定目标 3 将集中于利用生物分布研究、剂量测定对 131I-RhPBC 作为放射治疗进行体内评估 MMR 缺陷型结直肠癌小鼠模型的计算和纵向治疗研究。我们认为这个项目既具有高度创新性又具有高度影响力。据我们所知， DNA 错配以前从未成为核成像和治疗的目标，而八面体铑复合物尚未被用作放射性示踪剂的支架。从短期来看，这项工作可能会产生显像剂可能成为 MMR 缺陷肿瘤患者临床管理的有用工具。在从长远来看，这项研究还可能产生一种一流的放射治疗方法，可用于对抗多种 MMR 缺陷肿瘤，改善这些恶性肿瘤患者的预后和结果。