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（HNC）是毁灭性的。即使在可治疗疾病的情况下，每2例患者中有1个 诊断出最终屈服。此外，生存还使毒性具有使人衰弱的毒性。 辐射的毒性，导致生活质量差会增加抑郁症和自杀率。因此，有 开发精确肿瘤学方法的迫切需要，将辐射处理方法与HNC相匹配 生物学。 HPV相关（HPV+）HNC最常见于口咽（OPC），与很多相关 对辐射的敏感性更大。但是，多达20％的HPV+肿瘤患者也会因 辐射。相反，表达p16的HPV-HNC与真正的p16负相比暴露了有利的结果 肿瘤。该提案试图理解为什么这样做。具体而言，我们已经确定了蛋白质p16，a HPV的临床替代物，在其通常的细胞周期之外推动对辐射和PARP抑制的反应 调节功能，通过抑制DNA损伤修复（DDR）。 尽管通常认为p16在HPV+ HNC中在功能上不活跃，而在HPV-HNC中不存在，但我们的数据 表明p16通过HNC中的非规范信号传导起作用，以诱导BRCANESS状态，并且是关键 了解HPV+和HPV肿瘤中的差异辐射反应。在这个建议中，我们以 我们已经针对HNC中活跃的非典型P16介导的途径生成的大量数据 - 导致 Huwe1的上调，USP7的下调和DDR的转变 - 首先表征关系 在p16和sp1之间 顺铂和辐射结合后，HNC的途径以及HNC的结果，这是此的性质 相互作用尚不清楚。我们既将表征这种互动，又要利用最先进的方法 全球表征p16和sp1对HNC临床前模型中mRNA和蛋白质水平的影响 和患者肿瘤。然后，我们将全面研究DDR上的p16和sp1之间的关系 辐射或奥拉帕里（Olaparib 模型以及400 HPV+和HPV- OPC肿瘤在最大的中用顺铂和辐射均匀处理 迄今为止的同类人群。最后，我们将在临床开发中利用USP7抑制剂与 临床前模型中的辐射或PARP抑制。 该项目的完成将在HPV+和HPV-HNSCC下游建立结果的生物标志物 在p16中，将USP7评估为对辐射和olaparib敏感的可行目标，并确定新的目标 用于HNC的精密医学。