Redox imaging for breast cancer prognosis

氧化还原成像用于乳腺癌预后

• 批准号: 9303778
• 负责人: LIN Z LI
• 金额: $ 63.4万
• 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/9303778
• 关键词: Back; Benign; Biochemical; Biopsy; Breast Cancer Cell; Breast Cancer Model; 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; Cell physiology; 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; Metastatic to; Mitochondria; Molecular; Monitor; Mus; NADH; Needles; Neoplasm Metastasis; Nodal; Outcome; Oxidation-Reduction; Oxides; PTEN gene; Pancreas; Pathologic; Patients; Predictive Value; Premalignant; Procedures; Proteins; Publications; Reagent; Recurrence; Research; Research Personnel; Risk; Role; Specimen; TP53 gene; Techniques; Testing; Time; Tissue Banks; Transgenic Mice; Treatment outcome; Tumor Tissue; Work; Xenograft procedure; base; breast cancer diagnosis; breast imaging; cancer cell; cancer imaging; clinical Diagnosis; cohort; cost; disorder risk; fluorescence imaging; imaging biomarker; improved; in vivo; indexing; individualized medicine; interest; malignant breast neoplasm; melanoma; metabolic imaging; mitochondrial metabolism; mouse model; novel; novel strategies; optical imaging; outcome forecast; oxidative damage; personalized cancer therapy; 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（申请人提供）：目前的病理学指标无法准确预测个体癌症患者的治疗结局和复发/转移风险。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，无法用现有技术充分确定。有很大的兴趣和未满足的需求，在测试是否可以结合肿瘤线粒体代谢及其异质性的成像指标纳入乳腺癌的预后模型，以促进个性化治疗。本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（Fp，包括FAD）的荧光成像在管理乳腺癌（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，我们将确定线粒体氧化还原成像指标的BC患者的预后。我们将开发一种光学成像针装置，并在活体活检过程中获得实时氧化还原成像测量。我们将检验假设1a，即HMARI指数可以区分癌性（浸润性vs原位）、癌前病变和良性/正常乳腺组织。我们还将对自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BC的局部复发和转移的风险，并有可能增加当前临床预后模型的价值。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，我们将确定小鼠和细胞模型中预后氧化还原成像指数的代谢基础。我们将检验假设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BC小鼠异种移植物体内转移潜力相关，以及2）HAMRI指数与BC细胞系体外侵袭潜力相关。我们将用不同的生化试剂处理癌细胞来改变线粒体的氧化还原状态。我们将检验假设2b，即线粒体氧化还原状态的变化与BC侵袭/转移潜能的变化相关。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）建立HAMRI指数作为BC预后的快速（真实的时间可实现的）、低成本和独立的预测因子; 2）建立线粒体氧化还原状态作为BC进展到转移的关键因素。这些新的结果将对乳腺癌的治疗产生重大的临床影响，并可以扩展到其他不同形式的癌症。我们相信，随着进一步的发展，这项研究有可能重塑目前的BC预后模型，从而在乳腺癌的治疗和监测方面开辟新的、新颖的范式。