Artemin overexpression in oral cancer pain and carcinogenesis

Artemin 过度表达在口腔癌疼痛和癌变中的作用

• 批准号: 10475175
• 负责人: Donna G Albertson
• 金额: $ 53.63万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475175
• 关键词: Agonist; Animal Model; Attenuated; Behavior; Behavioral; Blocking Antibodies; Cancer Pain Management; Cancer Patient; Cations; Cell Line; Chronic; Clinical Trials; Cultured Cells; Data; Dose; Endothelin; Endothelin-1; Foundations; Future; Genes; Genomics; Goals; Growth; Human; Hypersensitivity; Immunohistochemistry; In Vitro; Incidence; Individual; Malignant Neoplasms; Measurable; Measures; Mechanics; Mediator of activation protein; Modeling; Mus; Nature; Neoplasm Metastasis; Nerve Endings; Nerve Growth Factors; Neurons; Nitroquinolines; Nociception; Nociceptors; Non-Malignant; Oncogenes; Oncogenic; Opioid; Oral; Oxides; Pain; Pathway interactions; Patients; Phenotype; Protein Family; Proteins; Quality of life; Questionnaires; Reporting; Research; Role; Sampling; Structure of trigeminal ganglion; TRPV1 gene; Testing; Work; Xenograft procedure; attenuation; autocrine; base; biological specimen archives; cancer pain; cancer therapy; carcinogenesis; combinatorial; effective therapy; experience; glial cell-line derived neurotrophic factor; improved; individualized medicine; innovation; malignant mouth neoplasm; member; mouse model; neutralizing antibody; novel strategies; oral tissue; overexpression; paracrine; precision medicine; receptor; relating to nervous system; side effect; spinal nerve posterior root; synergism; transcriptome; treatment response; tumor microenvironment; tumorigenesis

Oral cancer patients suffer severe chronic and mechanically-induced pain. Opioids are initially effective, but dose escalation is required and side effects reduce quality of life. The long-term goal is to improve management of oral cancer and oral cancer pain. Oral cancer pain is initiated and maintained in the cancer microenvironment. Some overexpressed cancer genes, oncogenes, can function in an autocrine manner to promote cancer and in a paracrine manner as cancer pain mediators. The ensemble of altered genes/pathways in a cancer dictates response to treatment, which motivates the use of combinatorial therapies tailored to the individual (precision medicine) to both treat the cancer and pain. The overall objectives of this application are to determine (a) whether artemin (ARTN), a gene overexpressed in oral cancer is an oral cancer oncogene, (b) whether ARTN is an oral cancer pain mediator and (c) whether antagonizing ARTN stops oral cancer and alleviates oral cancer pain. The central hypothesis is that there are oral cancer oncogenes that promote cancer and induce oral cancer pain. The rationale for this project is that proalgesic oncogenes could be targeted to treat cancer and pain. The central hypothesis will be tested by pursuing three specific aims: (1) Determine if ARTN is a proalgesic oncogene in human cancer; (2) Determine whether ARTN is an oncogene and a nociceptive mediator; and (3) Determine the potential to stop oral cancer and alleviate oral cancer pain by antagonizing proalgesic oncogenes. In the first aim, expression of ARTN will be assessed by immunohistochemistry in archival specimens from patients who completed the UCSF Oral Cancer Pain Questionnaire (UCSFOCPQ) to determine if expression is correlated with pain. The second aim will evaluate the function of ARTN as an oncogene by manipulating expression in cultured cells in vitro and in human xenograft mouse models. Whether ARTN is a pain mediator will be assessed by measuring nociception induced by manipulating expression of ARTN in animal models in the absence of cancer growth. For the third aim, the potential of antagonizing ARTN to stop cancer and cancer pain will be evaluated by anti-ARTN treatment of mouse xenograft and carcinogenesis models. The proposed research is innovative in the applicants' opinion, because it uses information gained from genomic analysis of oral cancers to identify putative oral cancer proalgesic oncogenes. The research is significant because it is expected to lay the foundation for future clinical trials assessing the utility of targeting ARTN for cancer treatment and attenuation of cancer pain. The work will motivate identification of additional proalgesic oncogenes to improve precision cancer pain management.

口腔癌患者遭受严重的慢性和机械性疼痛。阿片类药物最初是 有效，但需要增加剂量，副作用会降低生活质量。长期的 目标是改善口腔癌和口腔癌疼痛的管理。口腔癌疼痛始发 并维持在癌症的微环境中。一些癌症基因过度表达， 癌基因可以以自分泌方式和旁分泌方式发挥促进癌症的作用 作为癌症疼痛的中介人。癌症中改变的基因/通路的集合决定了 对治疗的反应，这促使使用针对 个人(精准医学)既能治疗癌症，又能治疗疼痛。这个项目的总体目标是 应用是确定(A)青蒿素(ARTN)，一种在口腔癌中过度表达的基因 是口腔癌癌基因，(B)ARTN是否是口腔癌疼痛介质，以及(C) 拮抗ARTN可阻止口腔癌，缓解口腔癌疼痛。中心假设是 有口腔癌癌基因可以促进癌症并引发口腔癌疼痛。这个 这个项目的基本原理是，致痛癌基因可以作为治疗癌症和疼痛的靶点。 中心假设将通过追求三个具体目标来检验：(1)确定ARTN是否是一个 (2)确定ARTN是否是癌基因和 伤害性介质；以及(3)确定阻止口腔癌和缓解口腔疾病的潜力 通过拮抗致痛癌基因而产生的癌痛。在第一个目的中，ARTN将表达为 用免疫组织化学方法检测完成手术的患者的档案标本 加州大学旧金山分校口腔癌痛问卷(UCSFOCPQ)以确定表达是否相关 带着痛苦。第二个目标是通过操纵来评估ARTN作为癌基因的功能。 在体外培养细胞和人异种移植小鼠模型中的表达。ARTN是否为 疼痛介体将通过测量操纵表达所诱导的伤害感来评估 ARTN在动物模型中没有肿瘤生长。对于第三个目标，潜在的 拮抗ARTN止癌止痛将通过抗ARTN治疗进行评估 小鼠异种移植和致癌模型。拟议的研究在以下方面具有创新性 申请人的意见，因为它使用从口腔癌基因组分析中获得的信息来 鉴定可能的口腔癌前痛性癌基因。这项研究具有重要意义，因为它 有望为未来的临床试验奠定基础，评估靶向ARTN治疗 癌症治疗和减轻癌症疼痛。这项工作将激励人们识别 额外的致痛癌基因，以改善精确的癌症疼痛管理。