MicroRNAs for monitoring tumor progression and predicting response to therapy

MicroRNA 用于监测肿瘤进展并预测治疗反应

• 批准号: 8700672
• 负责人: Lizhong Wang
• 金额: $ 19.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700672
• 关键词: 1 year old; Address; Age; Aging; Animal Model; Biological Assay; Biological Markers; Blood Circulation; Breast Cancer Cell; Cancer Patient; Cells; Clinical assessments; Consumption; Defect; Development; Diagnostic Neoplasm Staging; ERBB2 gene; Early Diagnosis; Ensure; Epithelial Cells; Estrogen Receptors; Ethnic Origin; Female; Food; Formalin; Foundations; Functional RNA; Gene Deletion; Gene Expression; Goals; Grant; Human; Immune; In Vitro; Individual; Investigation; Link; Lung; MCF7 cell; Mammary Neoplasms; Methodology; Methods; MicroRNAs; Molecular; Monitor; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Nuclear; Outcome; Paraffin Embedding; Patients; Pharmaceutical Preparations; Plasma; Population; Prevalence; Recurrence; Regulation; Reporting; Sample Size; Sampling; Screening for cancer; Serum; Somatic Mutation; Source; Staging; Testing; Tetanus Helper Peptide; Therapeutic; Time; Tissues; Tumor Suppressor Proteins; Tumor stage; Up-Regulation; Validation; Work; cancer cell; cancer therapy; human subject; improved; in vivo; innovation; malignant breast neoplasm; minimally invasive; mortality; mouse model; novel; patient population; public health relevance; response; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Background: MicroRNAs (miRs) are altered in breast tumors, influencing tumor development and progression. As miRs are remarkably stable in circulation, they also have enormous potential as non-invasive biomarkers for breast cancer. Indeed, circulating miRs have been detected in breast cancer patients, but interpretation of their relevance as minimally invasive biomarkers is limited by inconsistent results. Furthermore, the cellular source of circulating miRs and the molecular mechanisms regulating these potential miR biomarkers remain unclear. To address these issues, a highly relevant animal model for in vivo investigation of potential miR biomarkers was established. Aging mice with a Scurfy (sf) mutation of the X-linked tumor suppressor, Foxp3 (Foxp3sf/+), develop spontaneous breast cancer and tumor lung metastases. Analysis of circulating miRs in Foxp3sf/+ female mice revealed that plasma miR-200c/141 and miR-155 levels increase dramatically during tumor progression and lung metastasis, and these results were validated in a small population of breast cancer patients. Thus, these miRs appear as ideal candidates for novel biomarkers to detect the progression of human breast cancer and predict tumor response to therapies. Hypothesis and Goals: The central hypothesis is that circulating miR-200c/141 and miR-155 are useful biomarkers for early detection and prediction of tumor progression and therapeutic response. This hypothesis will be tested in three specific aims: 1) To validate potential miR biomarkers in a large patient population, 2) To determine the utility of the miR biomarkers in the early detection of tumor progression and prediction of therapeutic response, and 3) To elucidate the genesis and regulation of circulating miR biomarkers. Approach: First, the upregulation of the miR biomarkers identified in the Foxp3sf/+ mouse model will be validated in a large population of breast cancer patients using a TaqMan miR assay. The most optimal methods, materials, controls, and matched individuals will be used to ensure the statistical significance of this validation. Second, we will determine if the miR biomarkers are useful for the early detection of tumor progression, especially tumor metastasis. The utility of miR biomarkers in predicting response to treatments in breast cancer patients will be estimated by comparison with current biomarkers. Third, we will use FOXP3 Tet-off MCF7 cells to determine if miRs are released from breast cancer cells and regulated by FOXP3. The Foxp3sf/+ mouse model will be used to further investigate the cellular sources of circulating miR biomarkers. Innovation and Significance: This study will be the first to investigate 1) the utility of the miR biomarkers in predicting response o therapies, and 2) the mechanisms regulating circulating miR biomarkers during tumor progression in vivo. If confirmed, these miR biomarkers will provide non-invasive tools for improving outcomes and decreasing mortality in breast cancers with FOXP3 defects.

描述（由申请人提供）：背景：microRNA（miR）在乳腺肿瘤中发生了改变，从而影响了肿瘤的发育和进展。由于miR在循环中非常稳定，因此它们作为乳腺癌的非侵入性生物标志物也具有巨大的潜力。实际上，在乳腺癌患者中已经检测到循环中的miR，但是将其相关性解释为微创生物标志物受到不一致的结果的限制。此外，循环miR的细胞来源和调节这些潜在miR生物标志物的分子机制尚不清楚。为了解决这些问题，建立了一个高度相关的动物模型，用于对潜在的miR生物标志物进行体内研究。 X连锁肿瘤抑制剂Foxp3（Foxp3sf/+）的衰老小鼠（SF）突变，发展为自发的乳腺癌和肿瘤肺转移。对FOXP3SF/+雌性小鼠中循环miR的分析表明，血浆miR-200C/141和miR-155水平在肿瘤进展和肺转移过程中急剧增加，并且这些结果在少数乳腺癌患者中得到了验证。因此，这些miR似乎是新型生物标志物检测人乳腺癌进展并预测肿瘤对疗法的反应的理想候选者。假设和目标：中心假设是循环miR-​​200C/141和miR-155是早期检测和预测肿瘤进展和治疗反应的有用生物标志物。该假设将以三个具体目的进行检验：1）验证大型患者人群中潜在的miR生物标志物，2）确定miR生物标志物在早期检测到肿瘤进展和治疗反应的预测中的实用性，以及3）以阐明循环miR生物标志物的发生和调节。方法：首先，使用Taqman mir测定法，将在大量的乳腺癌患者中验证在FOXP3SF/+小鼠模型中鉴定出的miR生物标志物的上调。最佳方法，材料，控制和匹配的个体将用于确保统计意义 此验证。其次，我们将确定miR生物标志物是否对早期检测有用 肿瘤进展，尤其是肿瘤转移。通过与当前的生物标志物进行比较，将估计miR生物标志物在预测乳腺癌患者治疗反应的效用。第三，我们将使用FOXP3 Tet-Off MCF7细胞来确定MIR是否从乳腺癌细胞中释放出来并受Foxp3的调节。 FOXP3SF/+小鼠模型将用于进一步研究循环miR生物标志物的细胞来源。创新和意义：这项研究将是第一个研究1）MiR生物标志物在预测反应o疗法方面的效用，以及2）调节体内肿瘤进展过程中循环miR生物标志物的机制。如果得到证实，这些miR生物标志物将提供非侵入性的工具，以改善患有FOXP3缺陷的乳腺癌的结局和降低死亡率。