[R01] Optical hyperspectral nanoscale chromatin analysis for colon cancer risk-stratification
Ente: National Cancer Institute
Scadenza: 2030-04-30
Importo max: 655.526 EUR
Paese: US
Descrizione
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
Istituzione: NORTHWESTERN UNIVERSITY
PI: Vadim Backman, Hemant K. Roy, Igal G Szleifer
Progetto: 5R01CA289294-02
Settori: National Cancer Institute
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