Imaging and Targeting Metastatic-Prone Breast Cancer

易转移性乳腺癌的成像和靶向治疗

• 批准号: 8422419
• 负责人: Ronald George Blasberg
• 金额: $ 56.5万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-08 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422419
• 关键词: Animal Model; Bioluminescence; Breast Cancer Model; Cell Line; Cells; Characteristics; Complementary DNA; Data Set; Detection; Development; Disease; Enzymes; Evolution; Gene Expression; Genes; Growth; Growth and Development function; Human; Image; Label; Lactic acid; Link; Malignant Neoplasms; Mammary Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Molecular Profiling; Monitor; Mutation; Neoplasm Metastasis; Phenotype; Physiologic pulse; Primary Neoplasm; Production; RNA; Reporter; Research; Risk; Role; System; Techniques; Tissues; Transgenic Model; Tumor-Derived; Woman; cancer cell; cellular transduction; improved; interest; knock-down; lactate dehydrogenase A; magnetic resonance spectroscopic imaging; malignant breast neoplasm; mortality; neoplastic cell; non-invasive monitor; novel; outcome forecast; protein expression; public health relevance; response; small hairpin RNA; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; vector

DESCRIPTION (provided by applicant): Mortality in breast cancer, the most common malignancy in women, is usually caused by metastatic disease. This application focuses on the impact of changes in lactic acid metabolism on disease evolution, progression and development of metastases. This application focuses on two components of an abnormal metabolic phenotype in breast cancer involving lactate dehydrogenase A (LDH-A) and monocarboxylate transporter 4 (MCT4), because LDH-A is a bridge between several metabolic pathways and MCT-4 is primarily involved in the export of lactate from cancer cells. We propose to show that cells and tumors with high lactate secretion and/or tissue concentrations express high levels of LDH-A and MCT4, and that they are prone to be more invasive and to develop metastases. The expression of LDH-A and MCT4 are very highly correlated with the duration of metastasis-free survival in human breast cancer, and expression of these genes is expected to be highly correlated with tumor lactate concentrations. In addition, the product of LDH-A activity (lactate) can be assessed non-invasively and quantitatively using magnetic resonance spectroscopic (MRS) imaging (MRSI). Although lactate MRSI is not a new technique, the correlation with LDH-A and MCT4 gene expression and the non-invasive monitoring of LDH-A targeted therapy using lactate MRSI is novel. This research focus is supported by our expression profile analysis of genes involved in lactate metabolism in human breast cancer (see Fig. 1, Section 3.1), and strongly supports the rationale for this proposal. Our hypotheses are: 1) tumor lactate levels can be quantitatively assessed by MRSI; 2) tumor lactate levels will reflect corresponding levels of LDH-A and MCT4 expression, 3) tumor lactate, LDH-A and MCT4 are important components of the metabolic phenotype and have a major impact on the tumor microenvironment, tumor progression and the development of metastases; and 4) LDH-A inhibition can reduce breast cancer progression and reduce the development of metastases. Our Aims are: 1) Identify the associations between LDH-A, MCT4, lactate production, and the aggressive/ metastatic tumor phenotype in different orthotopic and transgenic models of breast cancer during tumor progression; and 2) Image and monitor the effects of LDH-A silencing/knock-down and determine the effect of lactate and pHe levels on tumor growth and development of metastases.

描述（由申请人提供）：乳腺癌是女性最常见的恶性肿瘤，其死亡率通常由转移性疾病引起。本申请的重点是乳酸代谢的变化对疾病演变、进展和转移发展的影响。本申请关注乳腺癌中异常代谢表型的两个组成部分，涉及乳酸脱氢酶A（LDH-A）和单羧酸转运蛋白4（MCT 4），因为LDH-A是几种代谢途径之间的桥梁，MCT-4主要参与乳酸从癌细胞的输出。我们建议表明，具有高乳酸分泌和/或组织浓度的细胞和肿瘤表达高水平的LDH-A和MCT 4，并且它们更容易具有侵袭性并发生转移。LDH-A和MCT 4的表达与人乳腺癌的无转移生存期高度相关，并且预期这些基因的表达与肿瘤乳酸浓度高度相关。此外，LDH-A活性的产物（乳酸盐）可以使用磁共振波谱（MRS）成像（MRSI）进行非侵入性和定量评估。虽然乳酸MRSI不是一项新技术，但乳酸MRSI与LDH-A和MCT 4基因表达的相关性以及使用乳酸MRSI对LDH-A靶向治疗的无创监测是新颖的。这一研究重点得到了我们对人类乳腺癌中乳酸代谢相关基因的表达谱分析的支持（见图1，第3.1节），并强烈支持了这一提议的基本原理。我们的假设是：1）肿瘤乳酸水平可以通过MRSI定量评估; 2）肿瘤乳酸水平将反映LDH-A和MCT 4表达的相应水平，3）肿瘤乳酸、LDH-A和MCT 4是代谢表型的重要组分，并且对肿瘤微环境、肿瘤进展和转移的发展具有重要影响;和4）LDH-A抑制剂可以减少乳腺癌的进展并减少转移的发展。我们的目标是：1）在肿瘤进展期间在乳腺癌的不同原位和转基因模型中鉴定LDH-A、MCT 4、乳酸盐产生和侵袭性/转移性肿瘤表型之间的关联;和2）成像和监测LDH-A沉默/敲低的影响，并确定乳酸盐和pHe水平对肿瘤生长和转移发展的影响。