Microvasculature in Colon Field Carcinogenesis: Clinical-Biological Implications

项目总结

Project Summary The overall goal of this project is to develop a rectal probe for minimally intrusive highly accurate risk stratification with the vision of utilizing it for a precision medicine approach to colon cancer screening and also potentially chemoprevention (companion biomarker). We will employ cutting edge biophotonics (ISOCT) and biological approaches combined with large scale human studies to elucidate the clinical/biological implications of mucosal early increase in blood supply (EIBS). Our multi-disciplinary group has extensively reported on EIBS in two animal models and human studies (n>1000) through the development of cutting-edge biophotonics technology namely the polarization gated spectroscopy (PGS) and more recently inverse spectroscopic optical coherence tomography (ISOCT). Clinically, rectal EIBS had excellent diagnostics of advanced adenomas (AUC >0.8) albeit impacted somewhat by race and gender. Biologically, our data on early colonic mucosal metabolic reprogramming (Warburg like effect) in both animal models and humans provides a potential mechanism for EIBS. For Causational Insights, pilot animal studies demonstrated that targeting microcirculation with the angiotensin receptor blocker losartan decreased EIBS with a concomitant suppression of colonic tumorigenesis. Furthermore, chemopreventive agents appear to reverse the Warburg-like physiology in the premalignant colonic mucosa. We hypothesize that EIBS is a manifestation of metabolic reprogramming that can be detectable with unprecedented accuracy with ISOCT. In aim 1 (technology), we will develop and validate the ISOCT fiberoptic probe and ascertain its accuracy for determining hemoglobin concentration, oxygenation status and blood vessel diameter at various superficial tissue depths. In aim 2 (biomarker), we will develop and validate a rectal EIBS prediction rule for the presence of advanced adenomas with prediction rule optimized for gender & race using biomarkers related to hemoglobin oxygenation, depth and blood vessel radius and density aiming for sensitivity & specificity ≥90%. For metabolic physiological correlates, we will interrogate the short term primary colon biopsy cell cultures via the extracellular flux analysis (Seahorse) as a physiological marker of Warburg. We will correlate with ISOCT readings and neoplasia presence (race/gender specific) along with the expressions of genes implicated in Warburg. In aim 3 (causational insight), we will perform animal studies to determine whether targeting the EIBS and secondary metabolic events using losartan (angiotensin 2 inhibitor) and metformin (promising chemopreventive agent known to reverse Warburg effects) would be a potential adenoma prevention strategy. Biologically, this study will provide definitive confirmation that EIBS is an important effector of metabolic reprogramming in colon carcinogenesis. Clinically, a rectal EIBS would be minimally intrusive and could be employed in the primary care setting to determine need for colonoscopy and also titrate or discontinue chemopreventive agents in order not to expose patients who do not derive a therapeutic benefit to the cost/toxicity of these agents. This new paradigm may herald the era of precision medicine in CRC prevention.