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

• 批准号: 9768982
• 负责人: Ginette Serrero
• 金额: $ 14.17万
• 依托单位: A AND G PHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768982
• 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; tumor; tumorigenesis

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）患者进行具有成本效益的微创疾病监测 疾病的进展或对治疗的反应是疾病临床管理中未满足的需求。成像 技术目前是这种监测的黄金标准。然而，关于 所需成像的类型和频率。影像学检查昂贵、耗时、发现疾病变化缓慢 并引起了对重复辐射暴露的关注，而且保险并不总是包括这些费用。 标准中使用了成像的补充方法，如循环肿瘤细胞和生物标志物。 护理（SOC），虽然它们的应用仍然有限。一个简单的，具有成本效益的血液测试，以衡量水平 作为疾病侵袭性驱动因素的生物标志物的研究应该为实时检测提供新的解决方案。 监测治疗反应，减少MBC人群对成像的依赖。PI已确定 一个88 kDa的糖蛋白GP 88（progranulin），阐明了其作为自分泌生长和存活的生物活性， 因子GP 88从癌细胞中分泌，在乳腺癌的生物液体中可测量到更高的水平 与健康人相比，基于这些特征，一种创新的诊断测试（酶 建立了测定循环中GP 88的免疫测定法（EIA）。我们的SBIR 1期回顾性研究 证明了EIA试验测定的血清GP 88水平与目的之间的统计学相关性。 疾病指标，即101例MBC患者的RECIST 1.1。我们确定血清GP 88水平为56 ng/mL， 是一个分层点，低于该点的患者总生存率提高，而GP 88>56 ng/ml的患者 结果很差。我们发现，血清GP 88水平与治疗反应在统计学上相关。 与SOC生物标志物CA 15 -3不同，CA 15 -3仅与疾病进展相关， 疾病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， 15个月期间，在两个临床地点招募120名MBC患者，每月测量血清GP 88水平 每3个月进行一次成像。目标是验证第一阶段的结果，并建立 GP 88检测在监测MBC患者疾病进展/缓解中的预测性用途，作为 成像并帮助对这些患者进行临床管理。具体而言，我们将（1）检测血清GP 88 水平与成像结果定义的疾病反应/进展相关;（2）检查 连续高（> 56 ng/mL）和低（<56 ng/mL）GP 88血液水平对未来反应/进展和时间的影响 （3）提示GP 88水平持续降低（<56 ng/mL）的患者 与GP 88血液水平持续高（> 56 ng/mL）的患者相比， 程度.该第2阶段的结果将是建立临床数据，以支持GP 88 EIA的商业化 作为MBC患者临床管理的组成部分，将有助于改善MBC患者的护理 以降低成本。