Characterization of biomarkers on circulating tumor cells to guide therapy

循环肿瘤细胞生物标志物的表征以指导治疗

• 批准号: 8056722
• 负责人: Richard H. Bruce
• 金额: $ 19.83万
• 依托单位: KRYPTOS MEDICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056722
• 关键词: Characterization; biomarkers; circulating; tumor; cells

DESCRIPTION (provided by applicant): Breast cancer-related death results from complications due to metastatic growth. Therapies for metastatic patients focus on extending survival and controlling symptoms, and the choice of therapies is frequently based on particular target-proteins found in the primary breast tumor, which is usually excised years before development of metastatic disease. Therapies for these target-proteins are much more effective in treating metastatic patients than standard chemotherapy. Because cancer changes over the time, the target-proteins in some metastatic tumors could well have changed from levels on the primary tumor. Biopsies that could test target proteins levels in metastatic tissue pose a problem because they are invasive, pose risk to the patient and are infeasible for patients with multiple different tumor sites. This proposal addresses locating tumor cells circulating in the blood and testing them for the target-proteins that help selection of a therapy. Because, circulating tumor cells (CTCs) represent the current metastatic disease, they arguably better represent metastatic disease than the primary tumor. Circulating tumor cells are rare and difficult to find. Current technologies used to find CTCs have problems. Some miss certain types of tumor cells due to low levels of expression of the enrichment target and provide poor images of the cells making it hard to be sure that they are CTCs. Others rely on size to find CTCs, but size varies widely, and such technologies miss small CTCs. In this work a research instrument, the FAST cytometer, uses an enrichment target that is known to be expressed at high levels in solid tumor cells. The assay does not degrade the cell morphology, and imaging is done on a planar surface for high fidelity. This proposal addresses the work needed to transform the research instrument into an instrument approved for use in a clinical trial. Methods will be developed to monitor the accuracy of the instrument and the multiplex assay. Procedures will be established to enable the CLIA certification needed for the clinical trial. The clinical trial will focus on metastatic breast cancer patients who have a triple negative primary tumor. Patients with this tumor type have no target-proteins and are ineligible to receive the targeted therapies. Consequently, they face a much poorer outcome. Preliminary data with a multiplex assay for 3 target-proteins has shown that target-proteins on CTCs are present in a significant number of patients. The clinical trial in Phase II will determine if these patients survive longer when the relevant target-therapies are administered. Clinical validation of the use of target protein levels on CTCs should enable more effective and personalized targeted therapy and prevention of acquired drug resistance, resulting in better response, improved progression-free and better overall survival. PUBLIC HEALTH RELEVANCE: Metastatic breast cancer can be optimally treated with special therapies that are selected by the presence of related proteins in the primary breast tumor, which is usually excised years before development of metastatic disease. As cancer is known to change over the time, the proteins in metastatic tumors could well be different. This proposal seeks to locate tumor cells circulating in the blood and determine in a clinical trial whether their proteins can better guide the selection of a therapy. The trial will focus on patients who have no special proteins on their primary tumors and hence face a worse outcome.

描述（由申请人提供）：与乳腺癌相关的死亡是由于转移性生长而引起的并发症。转移性患者的疗法专注于扩展生存和控制症状，并且疗法的选择经常基于原发性乳腺肿瘤中的特定靶标蛋白，这通常是在转移性疾病发展前几年切除的。这些靶蛋白的疗法在治疗转移性患者方面比标准化疗更有效。由于癌症随着时间的变化，因此某些转移性肿瘤中的靶蛋白可能会因原发性肿瘤的水平而改变。可以测试靶蛋白水平转移性组织中的活检会引起问题，因为它们具有侵入性，对患者构成风险，并且对于具有多个不同肿瘤部位的患者而言是不可行的。该提案解决了定位在血液中循环的肿瘤细胞，并测试了有助于选择治疗的靶蛋白。因为，循环肿瘤细胞（CTC）代表当前的转移性疾病，因此可以说，它们比原发性肿瘤更好地代表转移性疾病。循环肿瘤细胞很少见，很难找到。当前用于查找CTC的技术存在问题。一些人由于富集靶标的表达水平较低而错过了某些类型的肿瘤细胞，并提供了细胞的差图像，因此很难确保它们是CTC。其他人则依靠大小来查找CTC，但大小差异很大，此类技术会错过小型CTC。在这项工作中，一种研究工具，即快速细胞仪，使用了富集靶标，该目标已知在实体瘤细胞中以高水平表达。该测定不会降解细胞形态，并且成像是在平面表面上进行的，以实现高保真度。该提案解决了将研究工具转换为批准用于临床试验的工具所需的工作。将开发方法来监视仪器的准确性和多路复用测定法。将建立程序以实现临床试验所需的CLIA认证。临床试验将集中于具有三重阴性原发性肿瘤的转移性乳腺癌患者。这种肿瘤类型的患者没有靶蛋白，并且没有资格接受靶向疗法。因此，他们面临的结果要差得多。针对3种靶蛋白的多重测定的初步数据表明，大量患者存在于CTC上的靶蛋白。 II期的临床试验将确定在给予相关目标治疗时这些患者是否生存更长的时间。靶蛋白水平在CTC上使用的临床验证应使得更有效，个性化的靶向治疗以及预防获得的耐药性耐药性，从而获得更好的反应，改善无进展和更好的总体生存率。 公共卫生相关性：可以通过特殊疗法对转移性乳腺癌进行最佳治疗，这些疗法通过原发性乳腺肿瘤中相关蛋白的存在选择，这通常是在转移性疾病发展前几年切除的。随着癌症的变化，转移性肿瘤中的蛋白质可能会有所不同。该建议旨在定位在血液中循环的肿瘤细胞，并在临床试验中确定其蛋白质是否可以更好地指导选择治疗。该试验将重点关注那些在原发性肿瘤上没有特殊蛋白质的患者，因此面临较差的结果。