Optical hyperspectral nanoscale chromatin analysis for colon cancer risk-stratification - Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. despite being eminently preventable by colonoscopy. Colonoscopy is the gold standard of CRC screening. Its goal is to identify and remove premalignant adenomatous polyps with the advanced adenoma being the primary target. According to guidelines, colonoscopy is recommended for all patients over the age of 45 (roughly 100 million Americans). However, it is practically impossible to screen this entire eligible population with colonoscopy due to noncompliance, cost, and insufficient resources. As a result, less than half of the population receives colonoscopies as appropriate. The goal of this project is to develop a screening test to identify the subset of patients who harbor advanced adenomas and should undergo colonoscopy. The test must be accurate, low- cost, and can be carried out in the primary care setting. Despite significant interest in CRC screening, none of the existing or emerging tests has clinically practical sensitivity for advanced adenomas. We propose an alternate approach that bridges CRC field carcinogenesis as the biomarker source, dysregulation of chromatin conformation at the nanoscale as an etiological biomarker, and a new, AI-enhanced optical spectroscopic statistical nanosensing technology, which is uniquely positioned to enable detection of these subdiffractional and microscopically undetectable chromatin alterations. Our preliminary data show the feasibility of identifying patients who harbor advanced adenomas anywhere in the colon by the nanosensing of chromatin conformation alterations in colonocytes swabbed from the rectal mucosa. Our target is to achieve a negative predictive value of 99.5% with 95% sensitivity and 80% specificity for advanced adenomas, which would constitute a very high accuracy for a CRC screening test. The goal of the proposed project is to finalize the technology development, test it in a prospective clinical study, and bring it to the point where it is ready for definitive clinical validation. First, we will optimize optical nanosensing of chromatin, develop new methods of analysis of 3D chromatin scanning transmission electron tomography, deploy multi-label spectroscopic single molecule photolocalization nanoscopy for molecular nanoimaging of chromatin structure, and leverage computational electrodynamics and molecular dynamics simulations to link chromatin conformation alterations with transcriptional plasticity regulation in carcinogenesis and test the ability of spectroscopic nanosensing to identify these alterations. The technology will then be validated in a prospective clinical study. As our overarching goal, we envision that this screening test can be performed on any average-risk patient over the age of 45 as a first-line screening to identify patients who would benefit from colonoscopy. The test can be administered during a regular annual visit by a PCP. After a simple rectal swab with a cytology brush, the cells will be preserved and shipped to a centralized laboratory for chromatin nanosensing. This will increase the uptake of CRC screening with the goal of catchment of the entire eligible population while reducing unnecessary colonoscopies.
