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

总结 头颈部鳞状细胞癌（HNSCC）是全球第七大常见癌症。电流 治疗是病态的，即使对于治愈的患者，在美国有超过13，000例HNSCC死亡 每年。HPV阴性的HNSCC通常对DNA损伤治疗、EGFR抑制和免疫抑制具有抗性。 免疫疗法HPV相关的肿瘤对治疗有高度反应，但20- 30%会复发。即使有 免疫检查点抑制，这些患者中的大多数死亡。耶鲁大学头颈部孢子（YHN- SPORE）代表具有深厚疾病专业知识的高度转化研究人员，他们利用 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。 恶性肿瘤YHN-SPORE研究人员通过培训对HNSCC领域产生了重大影响， 转化和临床研究。基础科学家运用了严格的方法论。 YHN-SPORE旨在解决HNSCC治疗的关键障碍，这是由于对免疫，DNA 通过这些特定目的的损伤和靶向治疗：目的1：克服对EGFR抑制的抗性 目的2：通过靶向ErbB家族成员的活性构象， 目的3：探讨联合去甲基化治疗HPV阴性HNSCC的可行性 免疫检查点抑制疗法用于HPV介导的HNSCC的临床，机制研究， 目的4：通过我们的研究，为HNSCC研究奠定基础。 行政、生物标本和生物统计/生物信息学核心，以调动机构资源和 更广泛的SPORE社区;和目标5：推进新的研究和培养下一代HNSCC 翻译研究人员通过发展研究计划，职业发展计划， 与更广泛的SPORE和HNSCC研究社区的互动和合作。总主题 3个协调项目之一是克服治疗抗性， 目前的治疗方式和免疫疗法;翻译验证;人类终点，以支持未来 规避耐药性的新策略试验;相关研究中的机制确认;以及临床 在HPV阴性和HPV驱动的HNSCC中进行的试验。YHN-SPORE的预期转化结果为： (1)构象敏感的抑制剂，以克服HNSCC对EGFR抑制的耐药性;（2）临床安全性 和药效学数据结合极光A激酶/WEE 1抑制HPV阴性HNSCC;（3）证明- 概念和免疫分析数据，以支持联合去甲基化和免疫治疗的发展， HPV介导的HNSCC;（4）新的模型和基因组特征的肿瘤，使HNSCC翻译 研究;和（5）一个多样化的年轻研究人员谁将成为一代谁治愈HNSCC。

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.