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

• 批准号: 10666936
• 负责人: BARBARA BURTNESS
• 金额: $ 8.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10666936
• 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

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.

概括 头颈部鳞状细胞癌（HNSCC）是全球第七最常见的癌症。当前的 治疗是病态的，即使对于治愈的患者，HNSCC的美国有13,000多人死亡 每年。 HPV阴性HNSCC通常对DNA损害疗法，EGFR抑制和 免疫疗法。与HPV相关的肿瘤具有高度治疗的响应性，但复发20％至30％。即使有 免疫检查点抑制作用，大多数这些患者屈服。耶鲁的头和脖子孢子（YHN-- 孢子）代表具有基于疾病的深厚专业知识的高度转化研究人员 耶鲁癌症中心的非凡科学力量，以改善这种可怕的患者的治疗 恶性。 YHN-Spore的调查人员通过培训对HNSCC领域产生了重大影响，并且 翻译和临床研究。基础科学家带来严格的方法。 YHN-Spore试图解决由于对免疫，DNA的耐药性而治愈HNSCC的关键障碍 通过这些特定目的进行破坏和有针对性的治疗：目标1：克服对EGFR抑制的抵抗力 在HNSCC中，针对ERBB家族成员的主动构型；目标2：提高理性合成 HPV阴性HNSCC诊所的致命联合疗法；目标3：提高组合脱甲基化 对诊所的免疫检查点的治疗，用于HPV介导的HNSCC，机械研究和 免疫反应的表征；目标4：通过我们的HNSCC研究基础 行政，生物测量和生物统计学/生物信息学核心，以参与机构资源和 更广泛的孢子社区；目标5：进步新的研究并促进下一代HNSCC 通过发展研究计划，职业增强计划和 与更广泛的孢子和HNSCC研究社区的互动与合作。总体主题 在这三个协调的项目中，有克服治疗的抵抗力，涵盖了对阻力的机械洞察力 目前的治疗方式和免疫疗法；翻译验证；人类的终点是未来的基础 避免抵抗的新型策略的试验；相关研究中的机理确认；和临床 HPV阴性和HPV驱动的HNSCC试验。 YHN-Spore的预期翻译结果是： （1）构象敏感的抑制剂，以克服HNSCC中对EGFR抑制的抗性； （2）临床安全 HPV阴性HNSCC中的Aurora激酶/WEE1抑制作用和药效学数据合并了Aurora a aurora a激酶/WEE1； （3）证明 概念和免疫专长数据，以支持在 HPV介导的HNSCC； （4）新型模型和基因组序列化肿瘤可实现HNSCC翻译 研究; （5）一群年轻的调查员将成为治疗HNSCC的一代。