Analytical determination of biomarkers for diagnosis of breast cancer metastatic progression

癌症研究中的一个固有挑战是对癌症的基本信息进行编目， 通常是致命的转移性疾病。治疗转移性进展仍然是一个艰巨的任务， 由于无法监测允许癌症 在不同的组织类型中存活和生长。因此，一个重要的考虑因素是 从原发肿瘤生长到内脏器官的转移癌细胞。为了解决这个问题，我们 已经建立了等基因人转移性乳腺癌细胞系，其代表了 在乳腺癌患者中观察到的肺、骨、肝和脑的常见转移部位。我们的初步 对这些新的转移性细胞系的生物学评价强烈地表明，它们表现出位点-位点 表型差异最终反映了遗传多样性以及耐药性差异。在 此外，我们有初步的无标记拉曼光谱和代谢组学表征， 提供了明确的生物化学差异的客观证据，这些差异特异性地识别每个细胞， 线重要的是，我们对人类乳腺癌组织进行了无标记拉曼光谱分析 微阵列载玻片，并获得了明确的光谱生化标志，区分正常 转移性乳腺组织。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病灶的独特特征。 中心假设是，可以分配给位点特异性的分子标记的鉴定 乳腺癌转移病灶将促进最佳治疗策略，以增加总生存率。在 在本申请中，提出了三个具体目标来检验上述假设。在具体目标1中， 将建立新建立的同基因器官特异性转移性乳腺癌的拉曼光谱特征 体外培养的癌细胞在具体目标2中，我们将在以下临床前模型中验证拉曼光谱特征： 乳腺癌转移和匹配的原发性和转移性人乳腺癌样品。在特定 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。

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.