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，包括口腔癌和喉咙后部，是第六个最常见的癌症全世界。在美国，每年诊断出约50,000例新的口腔癌病例。第一的- 口腔癌的线治疗通常包括手术和放射线，并增加了化学疗法以减少转移后消除手术后残留肿瘤细胞的可能性，以提高辐射的效率（化学放疗），适用于确认远处转移的患者。辐射和口腔癌化学疗法会议会议细胞毒性主要是通过破坏DNA复制来诱导DNA损伤。不幸的是，口腔癌的预后，尤其是HPV（ - ）病例相对较差，呼吁更好地了解细胞如何应对复制应力和DNA损伤，因此，更有效的治疗选择和组合以克服耐药性。在当前项目中，我们表征了Greatwall（GWL）激酶在复制应力和DNA损伤反应中的新作用。 GWL 经常在HPV（ - ）口腔癌中进行更新，与癌症进展，肿瘤复发相关，和病人的生存不佳。 GWL促进了口腔癌细胞对影响的药物的恢复和抗性复制应力和DNA损伤。 GWL耗竭或抑制对口腔癌的药物反应敏感细胞和小鼠肿瘤模型。在这些发现的基础上，我们假设GWL介导了细胞对复制应力和DNA损伤的反应，因此是口腔癌治疗的潜在靶标。我们将发现GWL在复制应力中的功能和调节的详细机制， DNA损伤反应；我们还将为开发GWL建立关键的原则证明靶向癌症治疗。在AIM 1中，我们将描述如何通过其招募GWL来停滞叉子与复制蛋白A（RPA）相互作用以调节磷酸酶介导的对复制应激的反应。鉴于复制应力是标志，这项研究将为癌症进展和治疗提供新的启示癌症，抗复制药物通常用于癌症治疗。在AIM 2中，我们将透露一个新的在复制应力和DNA损伤后导致GWL稳定和积累的机制，有可能作为引发细胞恢复并承认肿瘤耐药性的关键事件。 GWL的上调是直接由DNA损伤信号传导介导，提示一种自动启动的“计时器”机制来启动细胞恢复和治疗耐药性。最后，在我们的机械调查的指导下，我们将在AIM 3中进行探索 GWL的治疗靶向，使用独特的小分子抑制剂，干扰任何一种GWL激酶激活或与RPA的相互作用。患者衍生的口腔肿瘤元素和原位同源性口服肿瘤模型将用于全面评估GWL抑制的治疗潜力。一起，该项目将使对复制应力和DNA的细胞反应有更深入的了解损害并表征了改善口腔癌疗法的新药物。