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Yale Head and Neck Cancer SPORE: Overcoming Treatment Resistance in Head and Neck Cancer

耶鲁头颈癌孢子：克服头颈癌的治疗耐药性

基本信息

批准号：
10441504
负责人：
BARBARA BURTNESS
金额：
$ 221.96万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441504
关键词：
Address Animals Basic Science Bioinformatics Biometry Cancer Biology Cancer Center Cell Line Cells Cellular biology Cessation of life Cetuximab Cisplatin Clinic Clinical Clinical Research Clinical Trials Collaborations Combined Modality Therapy Communities Core Facility Correlative Study DNA Damage Data Development Disease EGFR inhibition ERBB3 gene Epidermal Growth Factor Receptor Family Family member Fostering Foundations Fox Chase Cancer Center Funding Future Generations Genes Genomics HPV-negative head and neck cancer Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Human Human Papillomavirus Immune Immune response Immunology Immunotherapy Laboratories Link Malignant Neoplasms Mediating Mentors Methodology Modality Modeling Molecular Abnormality Molecular Conformation Mutation North Carolina Operative Surgical Procedures Outcome Pain Pathology Patients Pharmacodynamics Pharmacology Proteins Radiation Radiobiology Reproduction spores Research Research Personnel Resistance Resources Role Safety Sampling Scientist Signal Transduction Specimen System TP53 gene Training Translational Research Translations United States Universities Ursidae Family Validation Yale Cancer Center apolipoprotein B mRNA editing enzyme aurora kinase A barrier to care base career checkpoint inhibition conventional therapy curative treatments demethylating therapy demethylation functional disability improved inhibitor insight mortality new therapeutic target next generation novel novel strategies overtreatment polypeptide programs response structural biology targeted treatment therapy resistant translational scientist tumor virology

项目摘要

SUMMARY Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally. Current treatments are morbid, even for patients who are cured, and there are over 13,000 deaths in the US from HNSCC annually. HPV-negative HNSCC is commonly resistant to DNA damaging therapy, EGFR inhibition and immunotherapy. HPV-associated tumors are highly treatment-responsive, but 20-30 percent recur. Even with immune checkpoint inhibition, the majority of these patients succumb. The Yale Head and Neck SPORE (YHN- SPORE) represents highly translational researchers with deep disease-based expertise who leverage the extraordinary scientific strength at Yale Cancer Center, to improve treatment for patients with this terrible malignancy. YHN-SPORE investigators have significantly impacted the field of HNSCC through training, and translational and clinical research. Basic scientists bring rigorous methodology to bear. The YHN-SPORE seeks to address critical barriers to cure of HNSCC due to resistance to immune, DNA damaging and targeted therapy through these specific aims: Aim 1: To overcome resistance to EGFR inhibition in HNSCC by targeting active conformations of ErbB family members; Aim 2: To advance rational synthetic lethal combination therapy to the clinic in HPV-negative HNSCC; Aim 3: To advance combination demethylating therapy with immune checkpoint inhibition to the clinic for HPV-mediated HNSCC, with mechanistic studies and characterization of immune response; Aim 4: To bolster the foundation for HNSCC research through our Administrative, Biospecimen and Biostatistics/Bioinformatics cores, to engage institutional resources and the wider SPORE community; and Aim 5: To advance new research and to foster the next generation of HNSCC translational researchers through a Developmental Research Program, a Career Enhancement Program, and interaction and collaboration with the wider SPORE and HNSCC research communities. The overarching theme of the 3 coordinated projects is overcoming treatment resistance, spanning mechanistic insights into resistance to current treatment modalities and immunotherapy; translational validation; human endpoints to underpin future trials of novel strategies to circumvent resistance; mechanistic confirmation in correlative studies; and clinical trials in HPV-negative and HPV-driven HNSCC. Anticipated translational outcomes of the YHN-SPORE are: (1) conformationally sensitive inhibitors to overcome resistance to EGFR inhibition in HNSCC; (2) clinical safety and pharmacodynamic data combined aurora A kinase/WEE1 inhibition in HPV-negative HNSCC; (3) proof-of- concept and immunoprofiling data to support development of combined demethylation and immunotherapy in HPV-mediated HNSCC; (4) novel models and genomically-characterized tumors to enable HNSCC translational research; and (5) a diverse group of young investigators who will emerge as the generation who cure HNSCC.

总结