Imaging and Targeting Metastatic-Prone Breast Cancer

描述(申请人提供)：乳腺癌是女性最常见的恶性肿瘤，通常由转移性疾病引起。这一应用侧重于乳酸代谢变化对疾病演变、进展和转移发展的影响。这一应用主要集中在乳腺癌中一种异常代谢表型的两个组成部分，涉及乳酸脱氢酶A(LDH-A)和单羧酸转运体4(MCT4)，因为LDH-A是几个代谢途径之间的桥梁，而MCT-4主要参与癌细胞乳酸的输出。我们建议证明，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，并且它们易于更具侵袭性和发展转移。LDH-A和MCT4的表达与乳腺癌的无转移生存期高度相关，并且这些基因的表达有望与肿瘤乳酸浓度高度相关。此外，LDH-A活性的产物(乳酸)可以使用磁共振波谱成像(MRSI)进行非侵入性和定量的评估。虽然乳酸MRSI不是一项新技术，但利用乳酸MRSI与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的。这一研究重点得到了我们对人类乳腺癌乳酸代谢相关基因的表达谱分析的支持(见图1，3.1节)，并有力地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进行定量评估；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、肿瘤进展和转移发展具有重要影响；以及4)抑制LDH-A可以减缓乳腺癌的进展和转移的发展。我们的目标是：1)在不同的原位和转基因乳腺癌模型中，确定LDH-A、MCT4、乳酸的产生与肿瘤侵袭/转移表型之间的关系；以及2)成像和监测LDH-A沉默/敲除的影响，并确定乳酸和苯丙氨酸水平对肿瘤生长和转移的影响。

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.