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Greatwall in replication stress/DNA damage responses and oral cancer resistance

长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用

基本信息

批准号：
10991546
负责人：
Aimin Peng
金额：
$ 32.54万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2024
资助国家：
美国
起止时间：
2024-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10991546
关键词：
ATM activation Back Biochemical Biology Cell Cycle Cell Proliferation Cells Chemicals Cisplatin Clinical Collaborations DNA Damage DNA biosynthesis DNA replication fork Data Databases Dentistry Development Diagnosis Distant Metastasis Drug Sensitization Drug Targeting Drug resistance Event Fluorouracil Goals Head and neck structure Hour Human Papillomavirus Investigation Laboratories Ligase Malignant Epithelial Cell Malignant Neoplasms Mediating Mitosis Modeling Mouth Neoplasms Mus Neoplasm Metastasis Oncologist Operative Surgical Procedures Oropharyngeal Pathologist Pathway interactions Patients Pharmaceutical Preparations Pharyngeal structure Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Poly(ADP-ribose) Polymerase Inhibitor Process Prognosis Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Proteolysis Proteomics Publishing Radiation Recovery Recurrent tumor Regimen Regulation Residual Neoplasm Resistance Role Signal Transduction Squamous cell carcinoma Therapeutic Time Ubiquitination United States Up-Regulation biological adaptation to stress cancer cell cancer drug resistance cancer therapy cancer type chemoradiation chemotherapeutic agent chemotherapy clinical development college cytotoxicity effective therapy hydroxyurea improved in vivo inhibitor insight malignant mouth neoplasm mouth squamous cell carcinoma neoplastic cell new therapeutic target novel therapeutics recruit repaired replication factor A replication stress response small molecule inhibitor spatiotemporal targeted cancer therapy therapeutic target therapy resistant tumor tumor progression tumor xenograft

项目摘要

Oral cancer, including cancers of the mouth and the back of the throat, is the sixth most common cancer worldwide. In the United States, approximately 50,000 new oral cancer cases are diagnosed each year. First- line treatments for oral cancer typically include surgery and radiation, with chemotherapy added to decrease the possibility of metastasis, to eliminate residual tumor cells after surgery, to enhance the efficacy of radiation (chemoradiation), and for patients with confirmed distant metastasis. Radiation and oral cancer chemotherapeutics confer cytotoxicity largely by disrupting DNA replication to induce DNA damage. Unfortunately, the prognosis of oral cancer, particularly HPV(-) cases, remains relatively poor, calling for a better understanding of how cells respond to replication stress and DNA damage, and accordingly, developing more effective treatment options and combinations to overcome drug resistance. In the current project, we characterize a new role of Greatwall (Gwl) kinase in the replication stress and DNA damage responses. Gwl was frequently upregulated in HPV(-) oral cancer, in correlation with cancer progression, tumor recurrence, and poor patient survival. Gwl promoted the recovery and resistance of oral cancer cells to drugs that induce replication stress and DNA damage. Gwl depletion or inhibition sensitized the drug responses in oral cancer cells and mouse tumor models. Building on these findings, we hypothesize that Gwl mediates the cellular responses to replication stress and DNA damage, and is therefore a potent target for oral cancer therapy. We will uncover detailed mechanisms underlying the function and regulation of Gwl in the replication stress and DNA damage responses; we will also establish the crucial proof-of-principle for the development of Gwl targeting in cancer treatment. In Aim 1, we will delineate how Gwl is recruited to stalled replication forks via its interaction with replication protein A (RPA) to regulate a phosphatase-mediated response to replication stress. This study will shed new light on cancer progression and treatment, given that replication stress is a hallmark of cancer, and that anti-replication drugs are commonly used in cancer therapy. In Aim 2, we will reveal a new mechanism that leads to Gwl stabilization and accumulation after replication stress and DNA damage, potentially as a key event that initiates cell recovery and confers tumor resistance. Upregulation of Gwl is mediated directly by DNA damage signaling, suggesting a self-engaged “timer” mechanism that initiates cell recovery and treatment resistance. Finally, guided by our mechanistic investigations, we will explore in Aim 3 therapeutic targeting of Gwl, using unique small molecule inhibitors which interfere with either Gwl kinase activation or its interaction with RPA. Both patient-derived oral tumor xenograft and orthotopic syngeneic oral tumor models will be utilized to comprehensively evaluate the therapeutic potential of Gwl inhibition. Together, this project will lead to a deeper understanding of the cellular responses to replication stress and DNA damage, and characterize a new drug target to improve oral cancer therapy.

口腔癌，包括口腔癌和咽喉癌，是第六大常见癌症。国际吧在美国，每年大约有50，000例新的口腔癌病例被诊断出来。首先- 口腔癌的一线治疗通常包括手术和放射治疗，转移的可能性，消除术后残留的肿瘤细胞，提高放射治疗的疗效（化放疗），并适用于确诊远处转移的患者。放射与口腔癌化学治疗剂主要通过破坏DNA复制以诱导DNA损伤来赋予细胞毒性。不幸的是，口腔癌的预后，特别是HPV（-）病例，仍然相对较差，需要更好地了解细胞如何应对复制应激和DNA损伤，并相应地开发更有效的治疗选择和组合，以克服耐药性。在目前的项目中，我们描述了Greatwall（Gwl）激酶在复制应激和DNA损伤反应中的新作用。GWL 在HPV（-）口腔癌中经常上调，与癌症进展、肿瘤复发相关，患者生存率低。GWL促进口腔癌细胞的恢复和对诱导肿瘤细胞凋亡的药物的耐药性复制应激和DNA损伤。gwl缺失或抑制对口腔癌药物敏感性的影响细胞和小鼠肿瘤模型。基于这些发现，我们假设Gwl介导了细胞内因此，它是口腔癌治疗的有效靶点。我们将揭示Gwl在复制应激中的功能和调节的详细机制， DNA损伤反应;我们还将为GWL的发展建立关键的原理证明靶向治疗癌症。在目标1中，我们将描述Gwl是如何通过其与复制蛋白A（RPA）相互作用以调节磷酸酶介导的对复制应激的反应。这项研究将为癌症的进展和治疗提供新的线索，因为复制应激是一个标志。抗复制药物通常用于癌症治疗。在目标2中，我们将揭示一个新的在复制应激和DNA损伤后导致Gwl稳定和积累的机制，潜在地作为启动细胞恢复和赋予肿瘤抗性的关键事件。Gwl的上调是直接介导的DNA损伤信号，这表明一个自我参与的"计时器"机制，启动细胞恢复和治疗抗性。最后，在我们的机制研究的指导下，我们将在目标3中探索 Gwl的治疗靶向，使用干扰Gwl激酶的独特小分子抑制剂，激活或与RPA的相互作用。患者来源的口腔肿瘤异种移植物和原位同基因口腔肿瘤异种移植物两者都可以被移植。将利用肿瘤模型来综合评价Gwl抑制的治疗潜力。在一起，该项目将导致对细胞对复制应激和DNA的反应有更深的理解损伤，并表征一种新的药物靶点，以改善口腔癌治疗。