PathMAP NSCLC: A functional companion diagnostic test to predict optimal therapy for patients with non-small cell lung cancer.

PathMAP NSCLC：一种功能性伴随诊断测试，用于预测非小细胞肺癌患者的最佳治疗。

• 批准号: 9045159
• 负责人: Greg Bertenshaw
• 金额: $ 29.99万
• 依托单位: BIOMARKER STRATEGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045159
• 关键词: BAY 54-9085; Biological Markers; Biopsy; Cancer Diagnostics; Cancer Etiology; Categories; Cell Death Signaling Process; Cell Line; Cell Survival; Cells; Cessation of life; Classification; Clinic; Clinical; Collection; Conditioned Reflex; Diagnosis; Diagnostic tests; Disease; Disease Progression; Distant; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exposure to; Goals; Human; Individual; Life; Malignant neoplasm of lung; Medical; Methods; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphoproteins; Process; Proteins; Resistance; Sampling; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Solid Neoplasm; Survival Rate; System; Testing; Therapeutic; clinically actionable; companion diagnostics; follow-up; improved; in vivo; innovation; insight; instrument; neoplastic cell; public health relevance; resistance mechanism; response; tumor; user-friendly

 DESCRIPTION (provided by applicant): Lung cancer (LC) is the leading cause of cancer death in the US with an estimated 158,040 deaths in 2015. Non- small cell LC is the predominant category of the disease (NSCLC; 83%). Molecular characterization of tumors has shifted the paradigm of one drug fits all. Currently, molecularly-targeted agents (MTAs) and companion diagnostics (CDx) are being developed to target oncogenic drivers in signaling pathways, and select patients most likely to respond, respectively. This personalized approach was successful in increasing response rates (RR) to erlotinib by enriching for patients with EGFR activating mutations (68% RR versus 9% in unselected patients). Unfortunately, within a year for most patients, emergence of resistance mechanisms results in disease progression with little insight into appropriate follow-up therapy. In addition, many patients have no clinicaly- actionable biomarkers and are considered poor candidates for MTAs. However, many of these individuals can benefit from MTAs. Five-year survival rates are only 4% in patients with distant metastatic disease, when the disease is typically diagnosed. Therefore, there is an urgent medical need for improved predictive tests. Here, we propose to develop PathMAP(r) NSCLC, an innovative CDx test to predict the optimal therapeutic approach for patients with advanced NSCLC. This will be achieved by comparing the pharmacodynamic responses of signal transduction pathways upon exposure to four MTAs (erlotinib, crizotinib, trametinib and sorafenib) which target aberrantly activated proteins in these pathways. PathMAP NSCLC will be commerciality enabled using the SnapPath(r) Cancer Diagnostics System, the first and only user-friendly clinic-ready method, which automates and standardizes the interrogation of a patient's live tumor cells. Phase I Segment: Specific Aim #1: Optimize dispersion of NSCLC biopsies on the SnapPath instrument to prepare live cells for ex vivo modulation. 20 biopsies will be used to determine optimal SnapPath processing conditions. Flow rates and total cycles will be varied to enable equal distribution to multiple testing chambers without perturbing signaling and cell death. Specific Aim #2: Evoke Functional Signaling Profiles in NSCLC clinical samples against erlotinib. 30 biopsies will be profiled using the SnapPath Process. Milestones for transitioning to Phase II: 1. Effectively disperse and distribute clinical NSCLC biopsies on the SnapPath instrument. 2. Successfully generate functional profiles in >75% of the clinical samples. Phase II Segment: Specific Aim #3: Optimize ex vivo conditions and response profile to predict sensitivity to MTAs. 60 NSCLC cell lines will be categorized into sensitive or resistant groups and functionally profiled to create the PathMAP NSCLC model. Specific Aim #4: Test predictive ex vivo cut-off values using TumorGrafts and clinical NSCLC samples. The PathMAP NSCLC model will be used to predict MTA efficacy in 10 TumorGraft models and 200 human clinical samples from patients with metastatic NSCLC. These results are intended to be a proof-of-principle in humans.

 描述(申请人提供)：肺癌(LC)是美国癌症死亡的主要原因，2015年估计有158,040人死亡。非小细胞肺癌是该病的主要类型(非小细胞肺癌；83%)。肿瘤的分子特征已经改变了一种药物适用于所有人的范式。目前，分子靶向试剂(MTA)和伴随诊断(CDX)正在开发中，分别针对信号通路中的致癌驱动因素和选择最有可能反应的患者。这种个人化的方法通过丰富有EGFR激活突变的患者而成功地提高了对厄洛替尼的应答率(68%的应答率，而在未选择的患者中为9%)。不幸的是，对于大多数患者来说，在一年内，耐药机制的出现会导致疾病的进展，而对适当的后续治疗几乎没有洞察力。此外，许多患者没有临床可操作的生物标志物，被认为是MTA的糟糕候选者。然而，这些人中的许多人可以从多边贸易协定中受益。在诊断为远处转移性疾病的患者中，五年存活率仅为4%。因此，医学上迫切需要改进预测性测试。在这里，我们建议开发PathMAP(R)NSCLC，这是一种创新的CDX测试，用于预测晚期NSCLC患者的最佳治疗方法。这将通过比较四种MTA(erlotinib、crizotinib、trametinib和sorafenib)对信号转导通路的药效学反应来实现，这些MTA针对这些通路中异常激活的蛋白。PathMAP NSCLC将使用SnapPath(R)癌症诊断系统实现商业化。SnapPath(R)癌症诊断系统是第一种也是唯一一种用户友好的临床就绪方法，它可以自动化和标准化对患者活肿瘤细胞的询问。第一阶段：具体目标#1：优化SnapPath仪器上非小细胞肺癌活检的分散，为体外调节准备活细胞。将使用20次活组织检查来确定最佳SnapPath处理条件。流速和总周期将变化，以实现均匀分配到多个测试室，而不会干扰信号和细胞死亡。具体目标#2：在非小细胞肺癌临床样本中激发针对厄洛替尼的功能信号特征。30个活组织检查将使用SnapPath过程进行分析。过渡到第二阶段的里程碑：1.在SnapPath仪器上有效地分散和分发临床NSCLC活检。2.在75%的临床样本中成功生成功能配置文件。第二阶段：具体目标#3：优化体外条件和反应曲线以预测对MTA的敏感性。60个非小细胞肺癌细胞株将被归类为敏感或耐药 分组并从功能上进行配置以创建PathMAP NSCLC模型。具体目标#4：使用肿瘤移植和临床非小细胞肺癌样本测试预测的体外截断值。PathMAP NSCLC模型将用于预测10个肿瘤移植模型和来自转移性NSCLC患者的200个人类临床样本的MTA疗效。这些结果是为了在人类身上进行原则验证。