Redox imaging for breast cancer prognosis

氧化还原成像用于乳腺癌预后

• 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
• 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

 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（由适用提供）：当前的患者学指数无法准确预测单个癌症患者的复发/转移风险。肿瘤线粒体代谢及其在肿瘤内的异质性的程度是癌症进展的关键因素，无法通过现有技术充分确定。测试肿瘤线粒体代谢的成像指数的组合及其异质性是否可以纳入乳腺癌的预后模型以促进个性化治疗，这有很大的兴趣和未满足的需求。该项目的目的是证明线粒体氧化还原成像，即内源性NADH和氧化黄素蛋白的荧光成像（包括FAD）在管理乳腺癌（BC）中具有预后价值。我们的中心假设是，异质性相关的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。在第一个目标中，我们将确定患者BC预后的线粒体氧化还原成像指数。我们将开发一个光学成像的针头设备，并在活检过程中在体内获得实时的氧化还原成像测量。我们将检验假设1a，即HMARI指标可以在取消中有区别（在侵入性与我们还将在2008年以来收集的临床BC冻结样本进行回顾性进行氧化还原成像。我们将测试假设1b，假设1b，Hamri可以预测BC的位置复发和转移的风险，并添加了可能的临床，以便当前的PRIFTISTICS PRIFTISTICS PRIFTISTIC PRIFTISTICS添加了PRIFTISTIC，当前的临床水平。 1c Hamri可以在第二个目标中预测淋巴结状态，我们将在小鼠和细胞模型中确定预后的氧化还原成像指数的代谢基础。 BC细胞系在体外的侵入性潜力。我们将使用不同的生化试剂治疗癌细胞，以修饰线粒体氧化还原态。我们将测试假设2b，即线粒体氧化还原态的变化与BC的侵入性/转移潜力的变化相关。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）将Hamri指数建立为快速（可实现的），低成本和独立的BC预后预测指标； 2）将线粒体氧化还原状态确定为BC向转移的关键因素。这些新型结果将对乳腺癌管理产生重大临床影响，并可以扩展到其他不同形式的癌症。我们认为，随着进一步的发展，这项研究有可能重塑当前的BC预后模型，因此在治疗和监测乳腺癌方面开放了新的新型新型范式。