Targeting DNA Mismatches for Auger Electron Radiotherapy

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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.