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

摘要 头颈部鳞状细胞癌(HNSCC)是全球第七大常见癌症。当前 治疗是病态的，即使对治愈的患者也是如此，在美国有超过13,000人死于HNSCC 每年一次。HPV阴性的HNSCC通常对DNA损伤治疗、EGFR抑制和 免疫疗法。HPV相关肿瘤对治疗高度敏感，但20%-30%复发。即使是在 免疫检查点抑制，这些患者中的大多数都会屈服。耶鲁大学的头颈孢子(yhn- 孢子)代表了具有深厚疾病专业知识的高度翻译的研究人员，他们利用 耶鲁大学癌症中心非凡的科学实力，改善了对这一可怕患者的治疗 恶毒。YHN孢子研究人员通过培训对HNSCC领域产生了重大影响， 翻译和临床研究。基础科学家带来了严谨的方法论。 Yhn孢子寻求解决由于对DNA免疫耐药而治愈HNSCC的关键障碍 通过这些特定目标进行破坏性和靶向治疗：目标1：克服对EGFR抑制的耐药性 通过靶向ErbB家族成员的活性构象在HNSCC中；目标2：促进合理的合成 HPV阴性HNSCC致死联合治疗的临床应用；目标3：推进联合去甲基化 免疫检查点抑制治疗HPV介导的HNSCC的机制研究和临床应用 免疫反应的特征；目标4：通过我们的 行政、生物科学和生物统计/生物信息学核心，以利用机构资源和 更广泛的孢子界；和目标5：推进新的研究和培养下一代HNSCC 通过发展研究计划、职业提升计划和 与更广泛的孢子和HNSCC研究社区的互动和合作。最重要的主题 在3个协调的项目中，是克服治疗耐药性，跨越对耐药性的机械性见解 对当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的试验；相关研究的机制确认；以及临床 HPV阴性和HPV驱动的HNSCC的试验。YHN孢子的预期翻译结果是： (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 HPV阴性的HNSCC患者的药效学数据结合了aurora A Kinase/WEE1的抑制作用；(3) 用于支持联合去甲基化和免疫疗法发展的概念和免疫图谱数据 HPV介导的HNSCC；(4)新的模型和基因组学特征的肿瘤使HNSCC能够翻译 研究；以及(5)一群多样化的年轻研究人员，他们将成为治愈HNSCC的一代。

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.