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具有侵袭性的脑癌，预后不良，影响了大约20，000名新诊断的患者 美国患者每年人们对鉴定对已建立的免疫应答的预测性生物标志物非常感兴趣。 治疗，如替莫唑胺，并确定新的单一和组合的反应和耐药生物标志物 治疗胶质瘤，因为有证据表明，有效的辅助治疗策略可以提高生存率 患者的结果。目前存在很少的工具来识别这样的生物标志物并优先考虑施用哪种药剂 以最大限度地发挥药物治疗的作用。 我们将进行一项临床研究，在这项研究中，我们测量了一个队列中20种不同疗法的肿瘤反应， 32个病人仅使用外科手术程序，将可植入微型装置（IMD）放置到肿瘤中， 在已经安排的肿瘤切除术期间，肿瘤在手术期间保留在患者体内， 沿着切除的肿瘤标本。IMD能够读出每种治疗，包括免疫组织化学， 转录组学、免疫和组织生物标志物，从而有效地进行20项生物标志物试验， 每名患者的暴露水平，重复三次。 该项目将取得几项关键进展。一、安全性、可行性与临床技术整合 工作流程将以统计学显著的方式进行证明。这是建立更广泛临床应用的关键 这项技术在外科手术中的应用其次，我们将在回顾性分析中研究IMD是否 替莫唑胺（TMZ）储库的读数可作为标准全身TMZ治疗的预测标记 每例患者6个月时的缓解率和无进展生存率。这将是神经胶质瘤的一个重大进展 由于TMZ是这种疾病中最常给予的辅助治疗， 甲基化状态仅是TMZ对一部分胶质瘤患者疗效的有限预测因子。第三，我们将使用 多重最先进的深层组织表型分析，以表征每位患者肿瘤的生物学反应 分别接触微型装置上的20种药物。这将导致药物表型的全面目录， GBM患者的20种不同疗法，我们将使用这些数据系统地识别耐药途径， 可用的疗法。此外，通过检查肿瘤的遗传和生理变化，我们可以在体内将肿瘤的遗传和生理变化与肿瘤的生长相关。 肿瘤对多种药物反应的现有“组学”生物标志物。这解决了该领域的一个重大知识差距， 用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，以确定肿瘤微环境中的特定生物标志物， 对每种治疗的高和低表型反应。本研究将为证明局部瘤内 对微剂量多种药物的反应可用于有效筛选和定制神经胶质瘤的最佳治疗 患者评估IMD对治疗选择的预测价值为更广泛地使用IMD打开了大门， 医学和药物开发工具，以改善神经胶质瘤的结果。