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:
  • 金额:
    $ 45.76万
  • 依托单位:
  • 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

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.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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JOHN L HUMM其他文献

JOHN L HUMM的其他文献

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{{ truncateString('JOHN L HUMM', 18)}}的其他基金

Imaging drug uptake and distribution in chemoradiation therapy of pancreatic cancer
胰腺癌放化疗中的影像学药物摄取和分布
  • 批准号:
    9185682
  • 财政年份:
    2016
  • 资助金额:
    $ 45.76万
  • 项目类别:
124I-NaI PET: Building block for precision medicine in metastatic thyroid cancer
124I-NaI PET:转移性甲状腺癌精准医疗的基石
  • 批准号:
    9976468
  • 财政年份:
    2016
  • 资助金额:
    $ 45.76万
  • 项目类别:
124I-NaI PET: Building block for precision medicine in metastatic thyroid cancer
124I-NaI PET:转移性甲状腺癌精准医疗的基石
  • 批准号:
    9326954
  • 财政年份:
    2016
  • 资助金额:
    $ 45.76万
  • 项目类别:
124I-NaI PET: Building block for precision medicine in metastatic thyroid cancer
124I-NaI PET:转移性甲状腺癌精准医疗的基石
  • 批准号:
    9176730
  • 财政年份:
    2016
  • 资助金额:
    $ 45.76万
  • 项目类别:
Detection of Tumor Hypoxia by Non-invasive Nuclear Imaging Methods
无创核成像方法检测肿瘤缺氧
  • 批准号:
    7102435
  • 财政年份:
    2006
  • 资助金额:
    $ 45.76万
  • 项目类别:
Quantitative Imaging: Biostatistics and Medical Physics
定量成像:生物统计学和医学物理
  • 批准号:
    8555299
  • 财政年份:
    2000
  • 资助金额:
    $ 45.76万
  • 项目类别:
COMBINED RADIOIMMUNOTHERAPY WITH RADIOTHERAPY
放射免疫治疗与放射治疗相结合
  • 批准号:
    6497663
  • 财政年份:
    1999
  • 资助金额:
    $ 45.76万
  • 项目类别:
COMBINED RADIOIMMUNOTHERAPY WITH RADIOTHERAPY
放射免疫治疗与放射治疗相结合
  • 批准号:
    6350245
  • 财政年份:
    1999
  • 资助金额:
    $ 45.76万
  • 项目类别:
COMBINED RADIOIMMUNOTHERAPY WITH RADIOTHERAPY
放射免疫治疗与放射治疗相结合
  • 批准号:
    2843985
  • 财政年份:
    1999
  • 资助金额:
    $ 45.76万
  • 项目类别:
COMBINED RADIOIMMUNOTHERAPY WITH RADIOTHERAPY
放射免疫治疗与放射治疗相结合
  • 批准号:
    6150259
  • 财政年份:
    1999
  • 资助金额:
    $ 45.76万
  • 项目类别:

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  • 批准号:
    10794933
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    2022
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使用 FRET 开发 miRNA 和腺嘌呤甲基转移酶的诺贝尔检测方法
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DNA Methylation at N6-Adenine in Placental Trophoblast Development
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