Imaging and Targeting Metastatic-Prone Breast Cancer

描述（由申请人提供）：乳腺癌是女性中最常见的恶性肿瘤，其死亡率通常由转移性疾病引起。本应用侧重于乳酸代谢变化对疾病演变、进展和转移发生的影响。本应用主要关注乳腺癌异常代谢表型的两个组成部分，包括乳酸脱氢酶A （LDH-A）和单羧酸转运蛋白4 (MCT4)，因为LDH-A是几种代谢途径之间的桥梁，而MCT-4主要参与癌细胞的乳酸输出。我们提出，高乳酸分泌和/或组织浓度的细胞和肿瘤表达高水平的ldl - a和MCT4，并且它们更容易侵袭和发展转移。在人乳腺癌中，LDH-A和MCT4的表达与无转移生存期高度相关，预计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）可以使用磁共振成像（MRSI）进行无创和定量评估。虽然乳酸核磁共振成像不是一项新技术，但与ldl - a和MCT4基因表达的相关性以及使用乳酸核磁共振成像对ldl - a靶向治疗的无创监测是新颖的。我们对人乳腺癌中参与乳酸代谢的基因的表达谱分析支持了这一研究重点（见图1，Section 3.1），并有力地支持了这一建议的基本原理。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的LDH-A和MCT4表达水平；3)肿瘤乳酸、LDH-A和MCT4是代谢表型的重要组成部分，对肿瘤微环境、肿瘤进展和转移的发生有重要影响；4)抑制ldl - a可以减少乳腺癌的进展，减少转移的发生。我们的目标是：1)在肿瘤进展过程中，确定不同原位和转基因乳腺癌模型中ldl - a、MCT4、乳酸生成与侵袭性/转移性肿瘤表型之间的关系；2)成像和监测ldl - 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展的影响。

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.