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: 8829787
• 负责人: Ronald George Blasberg
• 金额: $ 56.23万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829787
• 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; Health; 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; response; small hairpin RNA; targeted imaging; targeted treatment; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; vector; 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; Health; 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; response; small hairpin RNA; targeted imaging; targeted treatment; 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）：乳腺癌死亡率是女性最常见的恶性肿瘤，通常是由转移性疾病引起的。该应用的重点是乳酸代谢对疾病进化，进展和转移发展的影响。该应用的重点是乳腺癌中异常代谢表型的两个成分，涉及乳酸脱氢酶A（LDH-A）和单羧酸酯转运蛋白4（MCT4），因为LDH-A是几种代谢途径和MCT-4之间的桥梁，主要参与乳酸细胞的乳酸细胞出口。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MCT4，并且它们容易发生更具侵入性并发展转移酶。 LDH-A和MCT4的表达与人类乳腺癌中无转移生存的持续时间非常高度相关，并且这些基因的表达与肿瘤乳酸浓度高度相关。此外，可以使用磁共振光谱（MRS）成像（MRSI）对LDH-A活性（乳酸）的乘积进行非侵入性和定量评估。尽管乳酸MRSI不是一种新技术，但使用乳酸MRSI的LDH-A和MCT4基因表达的相关性以及对LDH-A靶向治疗的非侵入性监测是新颖的。我们对人类乳腺癌中乳酸代谢涉及的基因的表达概况分析支持了这项研究重点（见图1，第3.1节），并强烈支持该提案的基本原理。我们的假设是：1）MRSI可以定量评估肿瘤乳酸水平； 2）肿瘤乳酸水平将反映相应水平的LDH-A和MCT4表达，3）乳酸肿瘤，LDH-A和MCT4是代谢表型的重要组成部分，对肿瘤微环境，肿瘤进展，转移酶的发展产生了重大影响； 4）LDH-A抑制作用可以减少乳腺癌的进展并减少转移的发展。我们的目的是：1）确定在肿瘤进展过程中不同的骨质和转基因模型中LDH-A，MCT4，乳酸产生和侵袭/转移性肿瘤表型之间的关联； 2）图像并监视LDH-A沉默/敲低的影响，并确定乳酸和PHE水平对肿瘤生长和转移发育的影响。