Label-Free Optical Redox Imaging for Pretreatment Prognosis of Early-Stage Triple Negative Breast Cancer

点击翻译按钮获取中文摘要

Label-Free Optical Redox Imaging for Pretreatment Prognosis of Early-Stage Triple Negative Breast Cancer Abstract Triple negative breast cancer (TNBC) has significant intratumor variations in microenvironments and metabo- lism, which can substantially affect disease progression and clinical outcomes. A TNBC tumor can contain hy- poxic and normoxic regions and exhibit glycolytic, oxidative, or mixed metabolic subtypes. These metabolic subtypes are typically on a submillimeter scale in clinically presented breast tumors, below the resolution of current clinical metabolic imaging methods, highlighting the need of new high-resolution metabolic imaging methods in the clinic. Optical Redox Imaging (ORI), a label-free fluorescence imaging technique developed at the Britton Chance Laboratory of Redox Imaging, can detect intratumor metabolic subtypes three- dimensionally (3D) with a resolution down to 25 µm. ORI measures the intrinsic fluorescence signals of re- duced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) and determines the oxidized and reduced status of redox metabolism. Our preliminary results found redox hotspots, the highly oxidized re- dox subtype in treatment-naïve specimens, from a pilot cohort of early-stage TNBC patients. Notably, in the studied cohort, ORI redox hotspots predicted the risk of disease progression better than conventional clinical indicators (e.g., tumor size, stage, grade, and nodal status). Our data studying untreated TNBC xenografts and cell cultures also suggested that the redox hotspots are underpinned by the Warburg effect (glycolytic switch), corroborating the prediction of risk of progression by ORI. Based on these results, the long-term goal of this program is to establish the prognostic value of pretreatment ORI by expanding observations in TNBC clinical specimens and preclinical models. Aim 1 will be a full-scale retrospective ORI study of frozen untreated surgi- cal specimens from early-stage TNBC patients. We will test the hypothesis that the intratumor redox hotspots predict an increased progression risk and add value to conventional prognostic indicators. Aim 2 will assess the prognostic value of ORI in human TNBC mouse xenografts and cultured cell models using progression endpoints and confirm that the activated glycolytic switch is the basis for the higher redox hotspot and risk of progression. The successful accomplishment of this project will establish ex vivo ORI as a novel pretreatment tool that is indicative of the intratumor glycolytic switch at submillimeter resolution and inform the risks of pro- gression for individual patients with early-stage TNBC. Our project will help resolve the unmet clinical need for accurate prognostic biomarkers to improve risk stratification and personalized treatment in TNBC.