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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.

项目摘要/摘要