Synthetic Lethal Therapy for HPV-Negative Head and Neck Cancer

HPV 阴性头颈癌的综合致死疗法

• 批准号: 10838999
• 负责人: BARBARA BURTNESS
• 金额: $ 7.41万
• 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/10838999
• 关键词: Address; Affect; Biomedical Research; Cancer Biology; Cell Cycle; Cell Death Induction; Cell Line; Cells; Cessation of life; Clinic; Combined Modality Therapy; Critical Thinking; DNA Damage; Development; Disease; Distant; Dominant Genetic Conditions; Genetically Engineered Mouse; Genotype; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Hispanic; Human Papillomavirus; Immune; In Vitro; Individual; Learning; Malignant Neoplasms; Mediating; Medical; Modeling; Mutate; Mutation; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphotransferases; Postbaccalaureate; Productivity; Prognosis; Publications; Research; Research Personnel; Research Training; Resistance; TP53 gene; Therapeutic; Tumor Suppressor Proteins; Work; Xenograft procedure; aurora kinase A; efficacy evaluation; experience; gain of function; graduate school; head and neck cancer patient; health care disparity; immune checkpoint blockade; improved; in vivo; inhibitor; innovation; kinase inhibitor; loss of function; medical schools; novel strategies; novel therapeutic intervention; patient derived xenograft model; pre-clinical assessment; response; response biomarker; skills; success; targeted treatment; trial design; underserved community

Project Abstract / Summary Head and neck squamous cell carcinomas (HNSCC) affect more than 890,000 individuals annually worldwide, and lead to over 450,000 deaths. Although significant progress has been made treating HNSCC including immune checkpoint blockade (ICB), intrinsic and adaptive resistance present great challenges to improving patient outcomes. In these cancers, the most dominant genetic alteration is mutation of the tumor suppressor TP53, which accounts for over 85% of patients. The Yale Head and Neck SPORE seeks to address critical barriers to cure of HNSCC due to resistance to immune, DNA damaging and targeted therapy. Our previous work identified synthetic lethality of inhibition of Aurora Kinase A (AURKA) and WEE1, a G2/M checkpoint kinase, leading to induction of cell death for HNSCC cell lines in vitro and xenografts and patient-derived xenografts in vivo. These innovative combinations of kinase inhibitors represent a completely new approach to treating TP53- mutated cancer. This study will help us to combination therapies to the clinic of HPV-negative HNSCC, particularly in the context of synthetic lethality and TP53mut-mediated drug response targeting cell cycle regulators. The proposed work will determine how different TP53 mutations affect drug response to AURKA inhibitor in combination with WEE1 inhibitor in HNSCC. Aim 1 will explore the relationship between TP53 mutation genotype and drug response to AURKA and WEE1 inhibitors in HPV-negative HNSCC cells. We will perform treatment combinations on isogenic cell lines with different TP53 genotypes including mutations strongly disruptive, weakly disruption, gain of function, loss of function and wild type. Aim 2 will preclinically assess the efficacy of the combinational treatment to generate response biomarkers and model potential trial design by using a new genetically engineered mouse model of HNSCC driven both by Tp53 and Cdkn2a mutations. This Diversity Supplement will provide Mr. Barrantes with an opportunity to learn and develop technical, communicative, and critical thinking research skills in the realm of cancer therapeutics. This supplement will also support additional pre-requisite coursework, and the opportunity for him to demonstrate his ability to complete graduate level coursework in the Yale Cancer Biology T32 Introduction to Cancer Biology Course. We expect his research success to include at least one scientific publication resulting from this project. Altogether, we anticipate that this research experience will provide Mr. Barrantes with opportunities for development as a productive researcher and more competitive application for medical or graduate school.

项目摘要/摘要 头颈部鳞状细胞癌(HNSCC)每年影响全球超过89万人， 并导致超过45万人死亡。尽管在治疗HNSCC方面取得了重大进展，包括 免疫检查点阻断(ICB)、固有和适应性抵抗对改进提出了巨大的挑战 病人的结果。在这些癌症中，最显性的基因改变是肿瘤抑制基因的突变。 TP53，占患者总数的85%以上。耶鲁大学头颈部孢子寻求解决关键问题 免疫抵抗、DNA损伤和靶向治疗是HNSCC治疗的障碍。我们以前的 工作确定了抑制Aurora Kinase A(AURKA)和WEE1的合成致死性，WEE1是一种G2/M检查点激酶， 在体外诱导HNSCC细胞系、异种移植瘤和患者来源的异种移植瘤细胞死亡 活着。这些创新的激酶抑制剂组合代表了一种治疗TP53的全新方法- 突变的癌症。本研究将有助于HPV阴性HNSCC的临床综合治疗。 尤其是在合成致死性和TP53mut介导的针对细胞周期的药物反应的背景下 监管者。拟议的工作将确定不同的TP53突变如何影响药物对AURKA的反应 联合应用WEE1抑制剂治疗HNSCC。目标1将探讨TP53与 HPV阴性HNSCC细胞中AURKA和WEE1抑制剂的突变基因型和药物反应。我们会 对具有不同TP53基因类型(包括强烈突变)的同基因细胞系进行治疗组合 破坏性、弱破坏性、功能获得、功能丧失和野生型。Aim 2将在临床前评估 联合治疗产生反应生物标记物的疗效和模型潜在试验设计 使用一种新的由TP53和CDKN2a突变驱动的HNSCC基因工程小鼠模型。这 多样性副刊将为巴兰蒂斯先生提供一个学习和发展技术的机会， 在癌症治疗领域具有沟通、批判性思维的研究技能。这份副刊还将 支持额外的必备课程，并让他有机会展示自己完成学业的能力 耶鲁癌症生物学T32癌症生物学导论课程的研究生课程。我们预计 他的研究成功地包括了至少一个由这个项目产生的科学出版物。总而言之，我们 预计这一研究经验将为Barrantes先生提供作为 多产的研究人员和更具竞争力的申请医学院或研究生院。