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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要即使在可治愈的疾病中，每 2 名患者中就有 1 名患有头颈癌 (HNC)。此外，幸存者在很大程度上由于中毒而死亡。辐射的毒性，导致生活质量差，因此出现抑郁症和自杀率增加。迫切需要开发与 HNC 的放射治疗方法相匹配的精准肿瘤学方法生物学。 HPV 相关 (HPV+) HNC 最常见于口咽部 (OPC)，并且与许多因素相关。然而，高达 20% 的 HPV+ 肿瘤患者也会因放射治疗而失败。与真正的 p16 阴性相比，表达 p16 的 HPV-HNC 表现出良好的结果。具体来说，我们已经确定了蛋白质 p16，这是一种肿瘤。 HPV 的临床替代品，可在其正常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) 来发挥调节功能。虽然 p16 通常被认为在 HPV+ HNC 中功能失活，并且在 HPV- HNC 中不存在，但我们的数据表明 p16 在 HNC 中通过非规范信号传导发挥作用，诱导 BRCA 状态，并且是关键为了了解 HPV+ 和 HPV- 肿瘤的放射反应差异，我们在此建议的基础上进行了研究。我们为 HNC 中活跃的非典型 p16 介导途径生成的大量数据 – 导致 HUWE1 的上调、USP7 的下调和 DDR 的转变——首先表征关系尽管我们已将 Sp1 与非规范 p16 信号传导的激活联系起来。途径，以及顺铂和放射组合后 HNC 的结果，这种情况的性质我们将描述这种相互作用并利用最先进的方法来描述这种相互作用。全面表征 p16 和 Sp1 对 HNC 临床前模型中 mRNA 和蛋白质水平的影响然后我们将全面检查p16和Sp1在DDR和患者肿瘤上的关系。使用免疫缺陷和功能正常的鼠原位组合进行放射或奥拉帕尼反应模型以及最大的 400 个 HPV+ 和 HPV- OPC 肿瘤均采用顺铂和放射治疗最后，我们将在临床开发中结合使用 USP7 抑制剂。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 下游结果的生物标志物 p16，评估 USP7 作为辐射敏感和奥拉帕尼的可行靶点，并确定新靶点用于 HNC 的精准医疗。