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

无标记光学氧化还原成像用于早期三阴性乳腺癌的预处理预后

基本信息

批准号：
10803898
负责人：
LIN Z LI
金额：
$ 67.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10803898
关键词：
3-Dimensional Adjuvant Therapy Affect Archives Biological Markers Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Cancer Prognosis Cell Culture Techniques Cell Respiration Cell model Cessation of life Clinic Clinical Cohort Studies Cultured Cells Data Data Set Dimensions Disease Disease Progression Exhibits Flavoproteins Fluorescence Freezing Future Genetic Glycolysis Goals Human Hypoxia Image Imaging Techniques Individual Label Laboratories Mammary Neoplasms Maps Measures Metabolic Metabolism Mission Molecular Mus Neoadjuvant Therapy Neoplasm Metastasis Nicotinamide adenine dinucleotide Nodal Operative Surgical Procedures Optics Outcome Oxidation-Reduction Patient-Focused Outcomes Patients Performance Phenotype Pilot Projects Pre-Clinical Model Prognosis Prognostic Marker Prospective Studies Public Health Receiver Operating Characteristics Recurrence Research Resolution Role Signal Transduction Specimen Stains Techniques Testing Time Training Tumor Volume United States National Institutes of Health Validation Variant Vascular blood supply Warburg Effect Xenograft Model Xenograft procedure cancer diagnosis cancer type clinical decision-making clinical imaging clinical translation cohort disorder risk fluorescence imaging high risk imaging biomarker imaging modality imaging study improved indexing individual patient innovation lung metastatic malignant breast neoplasm metabolic imaging metabolic phenotype metabolic profile metabolomics meter millimeter mouse model novel novel marker nutrition personalized medicine predict clinical outcome prognostic indicator prognostic model prognostic significance prognostic value prognostication programs progression risk risk prediction risk stratification tool treatment optimization treatment planning treatment strategy triple-negative invasive breast carcinoma tumor tumor metabolism tumor microenvironment tumor progression

项目摘要

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.

无标记光学氧化还原成像用于早期三阴性乳腺癌的预处理预后癌症抽象的三阴性乳腺癌（TNBC）在微环境和代谢方面具有显着的瘤内变化。 TNBC 肿瘤可能含有 hy- ，它可以极大地影响疾病进展和临床结果。含氧量和含氧量正常区域，并表现出糖酵解、氧化或混合代谢亚型。在临床表现的乳腺肿瘤中，亚型通常为亚毫米级，低于当前的临床代谢成像方法，凸显了新的高分辨率代谢成像的需求光学氧化还原成像（ORI），一种无标记荧光成像技术，由 Britton Chance 氧化还原成像实验室可以检测三种肿瘤内代谢亚型分辨率低至 25 µm 的三维 (3D) 测量重新的内在荧光信号。还原烟酰胺腺嘌呤二核苷酸 (NADH) 和氧化黄素蛋白 (Fp) 并测定氧化黄素蛋白我们的初步结果发现了氧化还原热点，即高度氧化的再-。值得注意的是，来自早期 TNBC 患者试点队列的未接受治疗的标本中存在 dox 亚型。研究队列中，ORI 氧化还原热点比传统临床更好地预测疾病进展风险我们研究未经治疗的 TNBC 异种移植物的数据。细胞培养还表明氧化还原热点是由 Warburg 效应（糖酵解开关）支撑的，基于这些结果，证实了 ORI 对进展风险的预测。该计划的目的是通过扩大 TNBC 临床观察来确定治疗前 ORI 的预后价值目标 1 将是对冷冻未经处理的手术进行全面回顾性 ORI 研究。我们将检验肿瘤内氧化还原热点的假设。预测进展风险增加，并为目标 2 评估的传统预后指标增加价值。 ORI 在人 TNBC 小鼠异种移植物和培养细胞模型中使用进展的预后价值终点并确认激活的糖酵解开关是较高氧化还原热点和风险的基础该项目进展的成功完成将使离体 ORI 成为一种新型预处理方法该工具以亚毫米分辨率指示肿瘤内糖酵解开关，并告知亲的风险我们的项目将有助于解决早期 TNBC 个体患者的未满足的临床需求。准确的预后生物标志物可改善 TNBC 的风险分层和个性化治疗。