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 头部和颈部鳞状细胞癌（HNSCCS）是一种侵略性的癌症形式，难以治疗 由于肿瘤的复杂性和异质性。对药物和放射疗法的抗性导致疾病 复发很常见，因为HNSCC在患者中是遗传上非常异质的。 HNSCC的研究 基因组，转录组和代谢组已揭示了新的靶标改变，但将这些发现转化为 治疗患者的临床改善是一条漫长的道路。因此，迫切需要创新 促进临床决策精确的策略。 Gevaert Lab（顾问）和Sunwoo的最新研究 实验室（Co-centor）表明，HNSCC可以分类为具有不同遗传和不同遗传和的各种亚型 表观遗传签名。迫切重要的是要知道这些亚型对标准的反应是否不同 护理治疗。该提案将测试患者衍生的肿瘤器官中的药物和辐射反应是否 （肿瘤）与这些患者的DNA甲基化模式相关。 AIM 1将建立高通量 通过在96和384孔板中精确的生物包裹瘤来生成自动化的HNSCC瘤瘤平台 自组装相同的瘤形成，该瘤将捕获患者的肿瘤异质性。 AIM 2将建立一个 使用18-F-氟脱氧葡萄糖（FDG）进行高通量瘤筛查的方法 用于癌症临床成像的放射性同位素。将肿瘤内的FDG涌入率与 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。 AIM 3将检查五个的护理标准和新兴治疗响应 异质HNSCC子组。我假设DNA（低/高）甲基化在HNSCC中起关键作用 对药物和免疫疗法的治疗耐药性。这些知识将大大改善未来的治疗 HNSCC患者的计划和总体存活率。此外，该项目将有两个重要的创新： 1）一种自动化的高通量策略，以生成用于药物，放射和免疫疗法的HNSCC瘤 筛选。 2）具有金色标准临床成像生物标志物的瘤瘤的高通量筛查策略， 用于准确评估治疗反应的诊所。这些创新将使更高 临床相关性，速度和自动化，同时降低测量和分析的可变性 基于器官的头颈癌研究。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，加强科学网络的知识和专业知识， 提高研究设计技能，并实现科学和专业的独立性。与成功 AIMS的完成，未来的潜在R01赠款将进一步推进该技术，以使其在临床上更加临床 相关且适合鉴定头颈癌的新药和免疫疗法靶标。总之， 该项目将使我们能够根据基于HNSCC亚型的护理标准治疗的敏感性 他们的表观遗传足迹和铺平了一种为这些患者开发有效而精确疗法的方法。