Analytical determination of biomarkers for diagnosis of breast cancer metastatic progression

用于诊断乳腺癌转移进展的生物标志物的分析测定

• 批准号: 9154551
• 负责人: Venu Raman
• 金额: $ 37.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9154551
• 关键词: Ablation; Address; Autopsy; Biochemical; Biological; Biological Markers; Brain; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Breast cancer metastasis; Carcinoma in Situ; Cataloging; Catalogs; Cell Line; Chemicals; Clinical; Coupled; Data; Databases; Disease; Disseminated Malignant Neoplasm; Drug Targeting; Drug resistance; Evaluation; Exhibits; FDA approved; Fatty acid glycerol esters; Genetic Variation; Goals; Growth; Histocompatibility Testing; Human; In Vitro; Knowledge; Label; Lesion; Liver; Lung; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Measurement; Metastatic breast cancer; Methods; Mining; Molecular; Molecular Profiling; Monitor; Neoplasm Metastasis; Organ; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological; Population; Pre-Clinical Model; Primary Neoplasm; Process; Proteomics; Quality of life; Raman Spectrum Analysis; Regimen; Research; Sampling; Site; Slide; Survival Rate; Testing; Tissue Microarray; Tissue Sample; Treatment Protocols; Visceral; anticancer research; base; bone; breast cancer diagnosis; cancer cell; clinically relevant; curative treatments; design; drug efficacy; efficacy testing; in vivo; innovation; malignant breast neoplasm; metabolomics; mouse model; neoplastic cell; personalized medicine; pre-clinical; proteomic signature; spectroscopic imaging; targeted treatment; treatment strategy; triple-negative invasive breast carcinoma; tumor microenvironment

An inherent challenge within cancer research is the cataloguing of fundamental information on what is generally fatal metastatic disease within vital organs. Treating metastatic progression remains a formidable task due to an inability to monitor specific differential molecular adaptations that allow for the cancer to survive and thrive within different tissue types. Hence, an important consideration is the divergence of the metastatic cancer cells growing in visceral organs from the primary tumor. To address this problem, we have established isogenic human metastatic breast cancer cell lines, which are representative of the common metastatic sites of lung, bone, liver, and brain observed in breast cancer patients. Our preliminary biological evaluations of these new metastatic cell lines strongly indicated that they exhibit site-to-site phenotypic distinctions that ultimately reflect genetic diversity as well as drug resistance differences. In addition, we have preliminary label-free Raman spectroscopy and metabolomic characterizations that provide objective evidence of the distinct biochemical differences that specifically identify each of the cell lines. Importantly, we have carried out label-free Raman spectroscopy on human breast cancer tissue microarray slides and obtained defined spectral biochemical signatures that differentiate normal from metastatic breast tissues. The importance of this finding is that we have now established objective molecular methods that will permit the identification of unique signatures of breast cancer metastatic lesions. The central hypothesis is that identification of molecular signatures that can be assigned to site-specific breast cancer metastatic lesions will facilitate optimal treatment strategies to increase overall survival. In this application, three specific Aims have been proposed to test the above hypothesis. In specific Aim 1, we will establish Raman spectral signatures of newly established isogenic organ-specific metastatic breast cancer cells in vitro. In specific Aim 2, we will validate Raman spectral signatures in preclinical models of breast cancer metastasis and in matched primary and metastatic human breast cancer samples. In specific Aim 3, we will determine chemotherapeutic efficacy of FDA approved oncological drugs in a site-specific manner based on Raman spectral signatures.

癌症研究中的一个内在挑战是对基本信息进行编目 通常致命的重要器官内的转移性疾病。治疗转移进展仍然是一项艰巨的任务 任务是由于无法监控允许癌症发生的特定差异分子适应 在不同的组织类型中生存和茁壮成长。因此，一个重要的考虑因素是 原发肿瘤内脏器官中生长的转移性癌细胞。为了解决这个问题，我们 已经建立了具有相同基因的人转移性乳腺癌细胞系，这是 乳腺癌患者常见的肺、骨、肝、脑转移部位。我们的预赛 对这些新的转移细胞系的生物学评价强烈表明，它们表现出点对点的特征。 最终反映遗传多样性和耐药性差异的表型差异。在……里面 此外，我们有初步的无标记拉曼光谱和代谢组学特征 提供明确识别每个细胞的不同生化差异的客观证据 台词。重要的是，我们已经对人类乳腺癌组织进行了无标记拉曼光谱 微阵列载玻片并获得明确的光谱生化特征，区分正常和 转移性乳房组织。这一发现的重要性在于，我们现在已经确立了目标 分子方法将允许识别乳腺癌转移性病变的独特特征。 中心假设是识别可以分配给特定部位的分子签名 乳腺癌转移性病变将有助于最佳治疗策略，以提高总体存活率。在……里面 在这一应用中，提出了三个具体的目标来检验上述假设。在具体目标1中，我们 将建立新建立的等基因器官特异性转移性乳房的拉曼光谱特征 体外培养的癌细胞。在特定的目标2中，我们将在临床前模型中验证拉曼光谱特征 乳腺癌转移以及配对的原发和转移性人类乳腺癌样本。具体而言 目的3，我们将确定FDA批准的肿瘤药物在特定部位的化疗效果 基于拉曼光谱特征的方式。