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