Redox imaging for breast cancer prognosis

氧化还原成像用于乳腺癌预后

基本信息

批准号：
8965104
负责人：
LIN Z LI
金额：
$ 66.27万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-02 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8965104
关键词：
Back Benign Biochemical Biopsy Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Breast biopsy Breast cancer metastasis Cancer Patient Cancer Prognosis Cancerous Cell Culture Techniques Cell model Cells Clinical Colon Carcinoma Coupled Data Decision Making Development Devices Disease Flavin-Adenine Dinucleotide Flavoproteins Fluorescence Free Radicals Freezing Goals Heterogeneity Human Image In Situ In Vitro Individual Malignant Neoplasms Mammary Gland Parenchyma Measurement Measures Mediating Metabolic Metabolism Metastatic to Mitochondria Monitor Mus NADH Needles Neoplasm Metastasis Nodal Outcome Oxidation-Reduction PTEN gene Pancreas Patients Premalignant Procedures Proteins Reagent Recurrence Research Research Personnel Risk Role Specimen Techniques Testing Time Tissue Banking Tissue Banks Transgenic Mice Treatment outcome Tumor Tissue Work Xenograft procedure base breast cancer diagnosis cancer cell cancer imaging cancer therapy clinical Diagnosis cohort cost disorder risk fluorescence imaging imaging biomarker improved in vivo indexing individualized medicine interest malignant breast neoplasm melanoma molecular size mouse model novel novel strategies optical imaging outcome forecast oxidative damage predictive modeling prognostic prognostic value public health relevance tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Current pathological indices cannot accurately predict the treatment outcome and the risk of recurrence/metastasis for individual cancer patients. The extent of tumor mitochondrial metabolism and its heterogeneity within the tumor are crucial factors in cancer progression that cannot be adequately determined with existing techniques. There are great interests and unmet needs in testing whether the combination of imaging indices of the tumor mitochondrial metabolism and its heterogeneity can be incorporated into the breast cancer prognostic models to facilitate individualized treatment. The objective of this project is to demonstrate that the mitochondrial redox imaging, i.e., fluorescence imaging of endogenous NADH and oxidized flavoproteins (Fp including FAD), has prognostic value in managing breast cancer (BC). Our central hypothesis is that the heterogeneity-associated mitochondrial redox imaging (HAMRI) indices (Fp, NADH and the redox ratios, e.g., Fp/NADH) can predict or add value for predicting BC prognosis. In the first aim, we will identify the mitochondrial redox imaging indices for BC prognosis in patients. We will develop an optical-imaging needle device and obtain real-time redox imaging measurements in vivo during the biopsy procedures. We will test hypothesis 1a that the HMARI indices can differentiate among cancerous (invasive vs in situ), premalignant and benign/normal breast tissues. We will also conduct redox imaging retrospectively on clinical BC frozen specimens collected since 2008. We will test hypothesis 1b that the HAMRI indices can predict the risk of local recurrence and metastasis of BC and have the potential to add value to current clinical prognostic model. Furthermore, we will test hypothesis 1c that HAMRI can predict nodal status. In the second aim, we will identify the metabolic basis for prognostic redox imaging indices in mouse and cell models. We will test hypothesis 2a that 1) the HAMRI indices correlate with the metastatic potential of BC mouse xenografts in vivo measured by fluorescence imaging of red fluorescence proteins in the metastases, and 2) the HAMRI indices correlate with the invasive potentials of BC cell lines in vitro. We will treat cancer cells with different biochemical reagents to modify th mitochondrial redox state. We will test hypothesis 2b that changes of the mitochondrial redox state correlate with the changes of invasive/metastatic potential of BC. We will also determine if these changes are associated with changes in the levels of free radicals and oxidative damages. Anticipated outcomes from this project include: 1) Establish the HAMRI indices as rapid (real time achievable), low-cost, and independent predictors of BC prognosis; 2) Establish the mitochondrial redox state as a key factor in BC progression to metastasis. These novel results will have significant clinical impact on breast cancer management and can be extended to other diverse forms of cancers. We believe that this research, with further developments, has the potential to reshape the current BC prognostic models and therefore, open new, novel paradigms in the treatment and monitoring of breast cancer.

描述（申请人提供）：目前的病理指标无法准确预测个体癌症患者的治疗结果和复发/转移的风险肿瘤线粒体代谢的程度及其在肿瘤内的异质性是癌症进展的关键因素，但无法充分预测。测试肿瘤线粒体代谢及其异质性的成像指标的组合是否可以纳入乳腺癌预后模型以促进个体化治疗存在很大的兴趣和未满足的需求。证明线粒体氧化还原成像，即内源性 NADH 和氧化黄素蛋白（Fp 包括 FAD）的荧光成像，在治疗乳腺癌 (BC) 方面具有预后价值。我们的中心假设是异质性相关线粒体氧化还原成像 (HAMRI) 指数。（Fp、NADH 和氧化还原比，例如 Fp/NADH）可以预测或增加预测 BC 预后的价值。我们将开发一种光学成像针装置，并在活检过程中获得体内实时氧化还原成像测量结果，我们将检验假设 1a，即 HMARI 指数可以区分癌性（侵袭性与癌性）。我们还将对 2008 年以来收集的临床 BC 冷冻标本进行回顾性氧化还原成像。我们将检验假设 1b，即 HAMRI 指数可以预测风险。此外，我们将检验假设 1c，即 HAMRI 可以预测淋巴结状态。在第二个目标中，我们将确定预后氧化还原成像指标的代谢基础。我们将在小鼠和细胞模型中检验假设 2a，即 1) HAMRI 指数与通过转移灶中红色荧光蛋白的荧光成像测量的体内 BC 小鼠异种移植物的转移潜力相关，以及 2) HAMRI 指数与体外 BC 细胞系的侵袭潜力相关。我们将用不同的生化试剂处理癌细胞以改变线粒体氧化还原状态。我们将检验假设 2b，即线粒体氧化还原状态的变化与侵袭/转移的变化相关。我们还将确定这些变化是否与自由基和氧化损伤水平的变化有关，该项目的预期结果包括： 1) 尽快建立 HAMRI 指数。（可实时实现）、低成本且独立的 BC 预后预测因子；2）将线粒体氧化还原状态确定为 BC 进展至转移的关键因素。这些新结果将对乳腺癌治疗产生重大临床影响，并可推广。我们相信，随着进一步的发展，这项研究有可能重塑当前的乳腺癌预后模型，从而为乳腺癌的治疗和监测开辟新的范例。