Using implantable microdevices for deep phenotyping of multiple drug responses in brain tumor patients

使用植入式微型设备对脑肿瘤患者的多种药物反应进行深度表型分析

• 批准号: 10732396
• 负责人: Oliver Jonas
• 金额: $ 74.68万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732396
• 关键词: Address; Adjuvant; Adjuvant Therapy; Adult; Adverse event; Affect; Apoptosis; Biological; Biological Markers; Biopsy; Brain; Brain Neoplasms; Cancer Patient; Cell Death; Cell Proliferation; Cells; Chemotherapy and/or radiation; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Combined Modality Therapy; DNA Damage; Data; Data Set; Development; Devices; Diffuse; Disease; Dose; Drug Catalogs; Drug Combinations; Drug Delivery Systems; Drug Exposure; Excision; Exposure to; Future; Genetic; Glioblastoma; Glioma; Goals; Head; Histologic; Immune; Immunologic Markers; Implant; In Situ; Intraoperative Complications; Knowledge; Length; MGMT gene; Malignant - descriptor; Malignant neoplasm of brain; Mass Spectrum Analysis; Measurable; Measurement; Measures; Metabolic; Methylation; Modeling; Molecular; Needle biopsy procedure; Newly Diagnosed; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phenotype; Physiological; Pilot Projects; Predictive Value; Procedures; Process; Prognosis; Progression-Free Survivals; Proteomics; Regimen; Resected; Resistance; Retrieval; Safety; Schedule; Selection for Treatments; Severities; Signal Pathway; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stromal Cells; System; Techniques; Technology; Testing; Tissues; Treatment Protocols; Tumor Markers; Work; biomarker identification; brain tumor resection; cancer type; chemotherapy; clinical decision-making; cohort; comparative; drug efficacy; drug response prediction; drug sensitivity; early detection biomarkers; effective therapy; functional status; implantation; improved; improved outcome; in vivo; individual patient; interest; metabolomics; microdevice; miniaturize; minimally invasive; multiple omics; novel therapeutics; optimal treatments; patient response; precision drugs; precision medicine; predicting response; predictive marker; promoter; response; response biomarker; safety and feasibility; specific biomarkers; standard of care; survival outcome; systemic toxicity; temozolomide; tissue biomarkers; tool; tool development; transcriptome; transcriptomics; treatment response; treatment strategy; tumor; tumor microenvironment

Gliomas are a particularly aggressive type of brain cancer with poor prognosis that affect about 20,000 newly diagnosed patients in the US annually. There is high interest in identifying predictive biomarkers of response to established treatments such as Temozolomide, and to identify response and resistance biomarkers for new single and combinations treatments for gliomas, as there is evidence that an effective adjuvant treatment strategy can improve survival outcomes for patients. Few tools exist currently to identify such biomarkers and prioritize which agent(s) to administer to individual patients in order to maximize the impact of drug treatment. We will conduct a clinical study in which we measure the tumor responses to 20 distinct therapies across a cohort of 32 patients. Using only intrasurgical procedures, implantable microdevices (IMD) are placed into tumors placed into tumors during already scheduled tumor resections, remain in the patient for the duration of surgery, and are extracted along with the resected tumor specimen. IMDs enable readouts for each treatment that include immunohistochemical, transcriptomic, immune and tissue biomarkers, thereby effectively performing 20 biomarker trials at minute drug exposure levels in each patient with three-fold replicates. Several key advances will be achieved in this project. First, safety, feasibility and clinical integration of the technical workflow will be demonstrated in a statistically significant manner. This is key towards establishing broader clinical use for this technology in the intrasurgical setting. Secondly, we will examine in a retrospective analysis whether the IMD readout at Temozolomide (TMZ) reservoirs can serve as a predictive marker for standard systemic TMZ treatment response and progression-free survival at 6 months for each patient. This would constitute a major advance for glioma patients, as TMZ is the most frequently administered adjuvant treatment in this disease, and the MGMT promoter methylation status is only a limited predictor of TMZ efficacy for a subset of glioma patients. Third, we will use multiplexed state-of-the-art deep tissue phenotyping to characterize the biological response of each patient’s tumor exposed to each of 20 drugs on the microdevice. This will result in a comprehensive catalogue of drug phenotypes for 20 distinct therapies in GBM patients, and we will use this data to systematically identify resistance pathways to available therapies. In addition, by examining the tumor for genetic and physiologic changes, we can in vivo correlate existing ‘omic’ biomarkers of tumor response to multiple drugs. This addresses a major knowledge gap in the field, as such a dataset is not feasible to obtain with traditional systemic clinical trials. The drug phenotyping includes spatial transcriptomics and metabolomics to identify specific biomarkers in the tumor microenvironment that correlate with high and low phenotypic response to each therapy. This study will lay the ground work to prove that local intratumor response to microdoses of multiple agents can be used to effectively screen for and tailor optimal treatment for glioma patients. Assessing the predictive value of the IMD for therapy selection opens the door to broader use as a precision medicine and drug development tool to improve outcomes in glioma.

神经胶质瘤是一种特别激进的脑癌类型，预后不良，影响约20,000个新诊断 每年在美国的患者。人们对确定对已建立的反应的预测生物标志物有很高的兴趣 诸如替莫唑胺之类的治疗方法，并确定新单一和组合的反应和抗性生物标志物 胶质瘤的治疗方法，因为有证据表明有效的调整治疗策略可以改善生存 患者的结果。目前，很少有工具来识别此类生物标志物并确定要管理哪些代理商 给个别患者，以最大程度地提高药物治疗的影响。 我们将进行一项临床研究，在其中测量跨组成的肿瘤对20种不同疗法的肿瘤反应 32例患者。仅使用外科手术程序，将可植入的微型设备（IMD）放入放入肿瘤中 在已经安排的肿瘤切除术中的肿瘤，在手术期间保留在患者中，并提取 IMD为包括免疫组织化学的每种治疗方法启用读数 转录组，免疫和组织生物标志物，从而有效地进行了20次生物标志物试验 每个患者的暴露水平具有三倍的重复。 该项目将取得几个关键的进步。首先，技术的安全性，可行性和临床整合 工作流将以统计学意义的方式进行证明。这是建立更广泛临床用途的关键 对于外部环境中的这项技术。其次，我们将在回顾性分析中检查IMD是否 Temozolomide（TMZ）储层的读数可以作为标准全身TMZ处理的预测标记 每位患者在6个月时的反应和无进展生存期。这将构成神经胶质瘤的重大进步 患者，因为TMZ是该疾病中最常见的调整治疗方法，而MGMT启动子 甲基化状态只是胶质瘤患者子集的TMZ效率的有限预测指标。第三，我们将使用 多重的最新深层组织表型，以表征每个患者肿瘤的生物学反应 暴露于微电位上的20种药物中的每种。这将导致全面的药物表型目录 GBM患者的20种不同疗法，我们将使用此数据系统地识别抗药性途径 可用的疗法。另外，通过检查肿瘤的遗传和生理变化，我们可以体内相关 肿瘤对多种药物的反应的现有“ OMIC”生物标志物。这解决了该领域的主要知识差距 通过传统的系统性临床试验获得这样的数据集是不可行的。药物表型包括空间 转录组学和代谢组学确定与肿瘤微环境中的特定生物标志物 对每种疗法的高表型反应。这项研究将奠定基础工作以证明当地的肿瘤 对多种药物的微剂量的反应可用于有效筛选和量身定制神经胶质瘤的最佳治疗 患者。评估IMD用于治疗选择的预测价值为更广泛使用的精确使用打开了大门 医学和药物开发工具可改善神经胶质瘤的预后。