A Circulating Biomarker for use in Monitoring Metastatic Breast Cancer

用于监测转移性乳腺癌的循环生物标志物

基本信息

批准号：
10477924
负责人：
Ginette Serrero
金额：
$ 7.08万
依托单位：
A AND G PHARMACEUTICAL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477924
关键词：
Applications Grants Biological Biological Markers Biological Process Blood Blood Circulation Blood Tests Blood specimen Breast Cancer Patient Caring Cessation of life Characteristics Clinical Clinical Data Clinical Management Clinical assessments Complement Consumption Data Dependence Diagnostic Diagnostic tests Disease Disease Management Disease Progression Disseminated Malignant Neoplasm Drug resistance Enrollment Enzyme Immunoassay Exposure to Frequencies Future Glycoproteins Gold Growth Health Image Imaging technology Individual Insurance Laboratories Liquid substance Longitudinal Studies Longitudinal prospective study Measurable Measurement Measures Metastatic breast cancer Monitor Neoplasm Circulating Cells Oncologist Outcome PGRN gene Patient Monitoring Patients Pharmaceutical Preparations Phase Population Process Quality of life Radiation Radiation exposure Recurrence Retrospective Studies Retrospective cohort Risk Sampling Scanning Schedule Serum Small Business Innovation Research Grant Stratification Testing Therapeutic Time Toxic effect Tumor Markers Tumor Tissue Work autocrine base cancer cell circulating biomarkers clinical examination clinical research site commercialization cost cost effective experience follow-up improved innovation malignant breast neoplasm minimally invasive novel patient population patient stratification predicting response prospective real time monitoring response standard of care treatment response tumor tumorigenesis

项目摘要

Cost-effective and minimally invasive monitoring of metastatic breast cancer (MBC) patients for disease progression or response to therapy is an unmet need in the clinical management of the disease. Imaging technologies are currently the gold standard of such monitoring. However, there is controversy regarding the type & frequency of imaging required. Imaging is expensive, time consuming, slow to detect disease changes and raises concern about repeated radiation exposure and costs are not always covered by insurance. Complementary approaches to imaging such as circulating tumor cells and biomarkers are used in the Standard of Care (SOC), although their application remains limited. A simple, cost-effective blood test to measure the level of biomarkers which are drivers of the disease aggressiveness should provide novel solutions for real-time monitoring of therapy response and reduce dependency on imaging in the MBC population. The PI has identified an 88kDa glycoprotein GP88 (progranulin), elucidated its biological activity as an autocrine growth & survival factor. GP88 is secreted from cancer cells and measurable in biological fluids at higher levels in breast cancer patients, compared to healthy individuals. Based on these characteristics, an innovative diagnostic test (Enzyme Immunoassay – EIA) to measure GP88 in circulation was established. Our SBIR Phase 1 retrospective study demonstrated a statistical association between serum GP88 levels measured by the EIA test and objective measures of disease, i.e. RECIST 1.1 in 101 MBC patients. We established that a serum GP88 level of 56ng/mL was a stratification point below which patients have improved overall survival while patients with GP88>56 ng/ml have a poor outcome. We showed that serum GP88 levels were statistically correlated to response to therapy in addition to progression of disease unlike the SOC biomarker CA15-3 which is only associated to progression of disease. Based on these promising data, we are proposing an SBIR Phase 2 prospective longitudinal study over a 15-month period enrolling 120 MBC patients at two clinical sites by measuring serum GP88 level every month with imaging performed every 3 months. The objectives are to validate the findings of phase 1 and establish the predictive use of the GP88 test in monitoring MBC patients for disease progression/ response as an adjunct to imaging and aid in the clinical management of such patients. Specifically, we will (1) Validate that serum GP88 levels are correlated to disease response/ progression as defined by imaging results; (2) Examine the impact of successive high (>56ng/mL) and low (<56ng/mL) GP88 blood levels on future response/ progression and time to progression as defined by imaging results; (3) Validate that patients with consistent low (<56ng/mL) GP88 blood levels, have improved survival compared with patients with consistently high (>56ng/mL) GP88 blood levels. The outcomes of this phase 2 will be to establish clinical data to support commercialization of GP88 EIA as an integral part of clinical management of MBC patients that will contribute to improved care of MBC patients at reduced cost.

对转移性乳腺癌 (MBC) 患者进行经济有效的微创疾病监测疾病进展或治疗反应是该疾病临床管理中未满足的需求。目前，技术是此类监控的黄金标准，但仍存在争议。所需成像的类型和频率昂贵、耗时且检测疾病变化缓慢。并引起人们对重复辐射暴露的担忧，而且费用并不总是由保险承担。标准中使用了补充成像方法，例如循环肿瘤细胞和生物标志物护理 (SOC)，尽管它们的应用仍然有限。一种简单、经济有效的血液测试来测量水平。作为疾病侵袭性驱动因素的生物标志物应该为实时提供新的解决方案 PI 已确定监测 MBC 人群的治疗反应并减少对影像学的依赖。 88kDa 糖蛋白 GP88（颗粒体蛋白前体），阐明了其作为自分泌生长和存活的生物活性 GP88 由癌细胞分泌，在乳腺癌的生物体液中可检测到较高水平。根据这些特征，将患者与健康个体进行比较，进行了创新的诊断测试（酶）。我们建立了测量循环中 GP88 的免疫测定法 (EIA)。我们的 SBIR 第一阶段回顾性研究已建立。 EIA 测试所测得的血清 GP88 水平与目标之间存在统计相关性我们确定 101 名 MBC 患者的血清 GP88 水平为 56ng/mL。是一个分层点，低于该点的患者总体生存率有所改善，而 GP88>56 ng/ml 的患者我们发现血清 GP88 水平与治疗反应存在统计学相关性。除了疾病的进展之外，与 SOC 生物标志物 CA15-3 不同，后者仅与疾病的进展相关基于这些有希望的数据，我们提出了一项 SBIR 2 期前瞻性纵向研究。在 15 个月的时间内，每月测量血清 GP88 水平，在两个临床中心招募 120 名 MBC 患者每 3 个月进行一次成像，目的是验证第一阶段的结果并建立 GP88 测试在监测 MBC 患者疾病进展/反应中的预测用途，作为辅助具体而言，我们将 (1) 验证血清 GP88。 (2) 考察影响连续高 (>56ng/mL) 和低 (<56ng/mL) GP88 血液水平对未来反应/进展和时间的影响根据影像学结果确定进展；(3) 验证 GP88 持续低（<56ng/mL）的患者与血液中 GP88 持续高浓度 (>56ng/mL) 的患者相比，生存率有所提高第二阶段的结果将是建立临床数据以支持 GP88 EIA 的商业化。作为 MBC 患者临床管理的一个组成部分，将有助于改善 MBC 患者的护理以降低的成本。