Novel OrganoPET Assay for Precision Therapy of Head and Neck Cancer

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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.