Novel OrganoPET Assay for Precision Therapy of Head and Neck Cancer

用于头颈癌精准治疗的新型 OrganoPET 检测

• 批准号: 10663731
• 负责人: Syamantak Khan
• 金额: $ 16.23万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663731
• 关键词: Automation; Biological Assay; Cancer Model; Classification; Clinic; Clinical; DNA; DNA Methylation; Data; Drug resistance; Ensure; Epigenetic Process; Future; Genetic; Genome; Grant; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Immunotherapy; Individual; Knowledge; Malignant Neoplasms; Measurement; Measures; Mentors; Methodology; Methylation; Organoids; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Positron-Emission Tomography; Precision therapeutics; Radiation; Radiation therapy; Radioisotopes; Recurrent disease; Research Design; Speed; Standardization; Subgroup; Survival Rate; Technology; Translating; Universities; Validation; anticancer research; bioprinting; cancer imaging; career development; clinical decision-making; clinical imaging; clinically relevant; drug testing; effective therapy; fluorodeoxyglucose; high throughput screening; imaging biomarker; improved; innovation; metabolome; methylation pattern; novel; novel therapeutics; prospective; radiation response; radiotracer; screening; self assembly; skills; standard of care; therapy resistant; transcriptome; treatment planning; treatment response; tumor; tumor heterogeneity; uptake

ABSTRACT Head and neck squamous cell carcinomas (HNSCCs) are an aggressive form of cancer that is difficult to treat due to the complexity and heterogeneity of the tumors. Resistance to drug and radiotherapy resulting in disease recurrence is common as HNSCCs are genetically very heterogeneous among patients. Studies of the HNSCC genome, transcriptome, and metabolome have revealed new altered targets, but translating these findings to clinical improvements in treating patients is a long road ahead. Therefore, there is a critical need to innovate strategies to facilitate precision in clinical decision-making. Recent studies by Gevaert Lab (Advisor) and Sunwoo Lab (Co-mentor) have shown HNSCCs can be classified into various subtypes with distinct genetic and epigenetic signatures. It is urgently important to know if these subtypes respond differently to the standard-of- care treatments. This proposal will test if the drug and radiation response in patient-derived tumor organoids (tumoroids) is correlated with DNA methylation patterns in these patients. Aim 1 will establish a high-throughput automated HNSCC tumoroid platform by precise bioprinting tumoroids in 96- and 384-well plates to generate self-assembled identical tumoroids, which will capture tumor heterogeneity of patients. Aim 2 will establish a methodology to perform high-throughput tumoroid screening using 18-F-Fluorodeoxyglucose (FDG), a radioisotope used for clinical imaging of cancer. The FDG influx rate inside tumoroids will be compared to the standardized uptake values (SUV) of the patient tumors (from positron emission tomography (PET) scans) for validation. Aim 3 will examine the standard-of-care and emerging treatment response among the five heterogeneous HNSCC subgroups. I hypothesize that DNA (hypo/hyper) methylation plays a key role in HNSCC treatment resistance to drugs and immunotherapy. This knowledge will significantly improve the future treatment plans and overall survival rate of HNSCC patients. In addition, this project will have two significant innovations: 1) An automated high-throughput strategy to generate HNSCC tumoroids for drug, radiation and immunotherapy screening. 2) A high-throughput screening strategy of tumoroids with gold-standard clinical imaging biomarkers, which are used in clinic for accurate assessment of treatment response. These innovations will enable higher clinical relevance, speed, and automation while reducing variability in both measurement and analysis in organoid-based head and neck cancer research. My career development activities at Stanford University will ensure gaining knowledge and expertise in head and neck cancer, bioprinting, strengthening scientific networks, improving study design skills, and achieving scientific and professional independence. With the successful completion of aims, a future prospective R01 grant will advance the technology further to make it more clinically relevant and suitable for identifying new drug and immunotherapy targets of head and neck cancers. In summary, the project will allow us to measure the sensitivity to standard-of-care treatments for HNSCC subtypes based on their epigenetic footprints and pave a way to develop an effective and precision therapy for these patients.

抽象的 头颈鳞状细胞癌 (HNSCC) 是一种难以治疗的侵袭性癌症 由于肿瘤的复杂性和异质性。对药物和放射治疗的抵抗导致疾病 复发很常见，因为 HNSCC 患者之间的遗传差异很大。 HNSCC的研究 基因组、转录组和代谢组揭示了新的改变目标，但将这些发现转化为 治疗患者的临床改进还有很长的路要走。因此，迫切需要创新 促进临床决策精确性的策略。 Gevaert Lab（顾问）和 Sunwoo 的最新研究 实验室（合作导师）已表明 HNSCC 可以分为具有不同遗传和特征的各种亚型 表观遗传特征。迫切需要了解这些亚型对标准的反应是否不同 护理治疗。该提案将测试患者来源的肿瘤类器官中的药物和放射反应是否 （肿瘤）与这些患者的 DNA 甲基化模式相关。目标 1 将建立高通量 自动化 HNSCC 类瘤平台，通过在 96 孔板和 384 孔板中精确生物打印类瘤来生成 自组装相同的肿瘤样物质，这将捕获患者的肿瘤异质性。目标 2 将建立一个 使用 18-F-氟脱氧葡萄糖 (FDG) 进行高通量肿瘤筛查的方法 用于癌症临床成像的放射性同位素。肿瘤样体内的 FDG 流入率将与 患者肿瘤的标准化摄取值（SUV）（来自正电子发射断层扫描（PET）扫描） 验证。目标 3 将检查五种疾病的护理标准和新出现的治疗反应 异质 HNSCC 亚组。我假设 DNA（低/高）甲基化在 HNSCC 中发挥关键作用 对药物和免疫疗法的治疗耐药性。这些知识将显着改善未来的治疗 HNSCC 患者的计划和总生存率。此外，该项目还将有两项重大创新： 1) 一种自动化高通量策略，用于生成 HNSCC 肿瘤样物质，用于药物、放射和免疫治疗 筛选。 2）具有金标准临床影像生物标志物的类肿瘤高通量筛选策略， 用于临床准确评估治疗反应。这些创新将实现更高 临床相关性、速度和自动化，同时减少测量和分析的可变性 基于类器官的头颈癌研究。我在斯坦福大学的职业发展活动将 确保获得头颈癌、生物打印、加强科学网络方面的知识和专业知识， 提高研究设计技能，实现科学和专业的独立性。随着成功的 完成目标后，未来的 R01 拨款将进一步推进该技术，使其更加临床化 相关且适合识别头颈癌的新药和免疫治疗靶点。总之， 该项目将使我们能够测量 HNSCC 亚型对标准护理治疗的敏感性 他们的表观遗传足迹，为为这些患者开发有效且精准的治疗方法铺平了道路。