Targeting non-canonical p16 signaling to improve radiation response and outcome in head and neck cancer

靶向非经典 p16 信号传导以改善头颈癌的放射反应和结果

• 批准号: 10733627
• 负责人: Heath Devin Skinner
• 金额: $ 59.84万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733627
• 关键词: Automobile Driving; BRCA1 gene; Biological Markers; Bypass; Cancer Biology; Cancer Control; Cancer Model; Cell Cycle; Cell Cycle Arrest; Cells; Cessation of life; ChIP-seq; Cisplatin; Clinical; Clinical stratification; Coupled; Cyclin-Dependent Kinase Inhibitor 2A; DNA Damage; DNA Repair; Data; Diagnosis; Disease; Down-Regulation; Exhibits; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune; Immunocompetent; Immunohistochemistry; Immunologic Deficiency Syndromes; In Vitro; Incidence; Left; Link; Mass Spectrum Analysis; Mediating; Mental Depression; Messenger RNA; Methodology; Modeling; Mus; Nature; Nonhomologous DNA End Joining; Oropharyngeal; Oropharyngeal Neoplasms; Outcome; PARP inhibition; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Proteins; Quality of life; Radiation; Radiation Toxicity; Radiation therapy; Recurrence; Repression; Resistance; Salivary; Signal Pathway; Signal Transduction; Sp1 Transcription Factor; Suicide; Survivors; Testing; Toxic effect; Up-Regulation; Work; arm; brca gene; cancer cell; clinical development; cohort; genetic signature; head and neck cancer patient; homologous recombination; improved; in vitro Assay; inhibitor; mouse model; novel; novel therapeutics; oral HPV-positive head and neck cancers; overexpression; precision medicine; precision oncology; radiation response; response; standard of care; therapy resistant; transcriptome sequencing; treatment response; tumor; ubiquitin-protein ligase; ubiquitin-specific protease

PROJECT SUMMARY Head and neck cancer (HNC) is devastating. Even in the setting of curable disease, 1 of every 2 patients diagnosed ultimately succumb. Additionally, survivors are left with debilitating toxicity due in large part to the toxicity of radiation, leading to poor quality of life increased rates of depression and suicide. Therefore, there is a critical need to develop precision oncology approaches which match radiation treatment approaches to HNC biology. HPV-associated (HPV+) HNC most commonly arises in the oropharynx (OPC) and is associated with much greater sensitivity to radiation. However, up to 20% of patients with HPV+ tumors will also be failed by radiation. Conversely, HPV- HNC that express p16 exhibit favorable outcomes compared to truly p16 negative tumors. This proposal seeks to understand why this is so. Specifically, we have identified the protein p16, a clinical surrogate for HPV, to be driving response to radiation and PARP inhibition outside of its usual cell cycle regulatory function, by inhibiting DNA damage repair (DDR). Although p16 is generally thought to be functionally inactive in HPV+ HNC, and absent in HPV- HNC, our data suggests that p16 is functioning via non-canonical signaling in HNC to induce a state of BRCAness and is key to understanding the differential radiation response in HPV+ and HPV- tumors. In this proposal we build upon the substantial data we have generated for a non-canonical p16-mediated pathway active in HNC – leading to upregulation of HUWE1, downregulation of USP7 and a shift in DDR – by first characterizing the relationship between p16 and Sp1. Although, we have linked Sp1 to the activation of our non-canonical p16 signaling pathway, as well as outcome in HNC following the combination of cisplatin and radiation, the nature of this interaction is unclear. We will both characterize this interaction as well as utilize state-of-the-art methodology to globally characterize the effects of p16 and Sp1 on mRNA and protein levels within HNC pre-clinical models and patient tumors. We will then comprehensively examine the relationship between p16 and Sp1 on DDR and radiation or Olaparib response using a combination of immunodeficient and -competent murine orthotopic models as well as 400 HPV+ and HPV- OPC tumors treated uniformly with cisplatin and radiation in the largest cohort of its kind to date. Finally, we will utilize USP7 inhibitors in clinical development in combination with either radiation or PARP inhibition in pre-clinical models. Completion of this project will establish biomarkers of outcome in both HPV+ and HPV- HNSCC downstream of p16, evaluate USP7 as a viable target for sensitization to radiation and Olaparib, and identify novel targets for precision medicine in HNC.

项目摘要 头颈癌（Head and Neck Cancer，HNC）是一种恶性肿瘤。即使在可治愈疾病的情况下，每2名患者中就有1名 最终被诊断出死亡。此外，幸存者留下了使人衰弱的毒性，这在很大程度上是由于 辐射毒性导致生活质量下降，抑郁症和自杀率上升。因此有 迫切需要开发与HNC放射治疗方法相匹配的精确肿瘤学方法 生物学 HPV相关（HPV+）HNC最常见于口咽（OPC），与许多疾病相关。 对辐射更敏感。然而，高达20%的HPV+肿瘤患者也会失败， 辐射相反，与真正p16阴性相比，表达p16的HPV- HNC表现出有利的结果 肿瘤的本建议试图理解为什么会这样。具体来说，我们已经确定了蛋白质p16， HPV的临床替代物，在其通常的细胞周期之外驱动对辐射和PARP抑制的反应 通过抑制DNA损伤修复（DDR）来调节功能。 虽然p16在HPV+ HNC中通常被认为是功能上无活性的，并且在HPV- HNC中不存在，但我们的数据显示， 表明p16通过HNC中的非经典信号传导发挥作用，诱导BRCAness状态，并且是关键 了解HPV+和HPV-肿瘤的不同辐射反应。在本建议中，我们建立在 我们已经产生了大量的数据，用于在HNC中激活的非经典p16介导的途径-导致 HUWE 1的上调，USP 7的下调和DDR的转变-通过首先表征 p16和Sp1之间的关系。尽管如此，我们已经将Sp1与我们的非经典p16信号传导的激活联系起来， 途径，以及顺铂和放射联合治疗后HNC的结局，这种作用的性质 相互作用不清楚。我们将描述这种相互作用，并利用最先进的方法， 在HNC临床前模型中全面表征p16和Sp1对mRNA和蛋白水平的影响 患者肿瘤。然后，我们将全面研究DDR上p16和Sp1之间的关系， 使用免疫缺陷和免疫活性鼠原位杂交的组合的放射或奥拉帕尼应答 模型以及400例HPV+和HPV- OPC肿瘤均用顺铂和放射治疗， 迄今为止的同类队列。最后，我们将在临床开发中使用USP 7抑制剂， 在临床前模型中的辐射或PARP抑制。 该项目的完成将建立HPV+和HPV- HNSCC下游结局的生物标志物 评估USP 7作为放射和奥拉帕尼致敏的可行靶点，并确定新靶点 在HNC的精准医疗