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.

口腔癌患者患有严重的慢性和机械诱发的疼痛。阿片类药物最初是 有效，但需要剂量升级，副作用降低了生活质量。长期 目标是改善口腔癌和口腔癌疼痛的治疗。口腔癌疼痛开始 并保持在癌症微环境中。一些过表达的癌症基因， 癌基因，可以以自分泌方式发挥作用，以促进癌症和旁分泌。 作为癌症止痛介质。癌症中改变基因/途径的合奏决定了 对治疗的反应，这激发了使用量身定制的组合疗法的使用 个体（精度医学）治疗癌症和疼痛。总体目标 应用是确定（a）Artemin（Artn）是否过表达口腔癌的基因 是口腔癌癌基因，（b）ARTN是否是口腔癌止痛药，（c）是否是 对抗ARTN会阻止口腔癌，并减轻口腔癌的疼痛。中心假设是 有口腔癌癌基因促进癌症并诱发口腔癌疼痛。这 该项目的理由是，促肿瘤基因可以针对治疗癌症和疼痛。 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 人类癌症中的果质癌基因； （2）确定ARTN是否是癌基因和 伤害性调解人； （3）确定阻止口腔癌和减轻口腔的潜力 癌症疼痛通过拮抗促阳性癌基因。在第一个目标中，Artn的表达将是 通过档案标本中的免疫组织化学评估完成的患者 UCSF口腔癌疼痛问卷（UCSFOCPQ）确定表达是否相关 痛苦。第二个目标将通过操纵ARTN作为癌基因的功能 体外和人异种移植小鼠模型中培养的细胞中的表达。 Artn是否是 通过测量操纵表达引起的伤害感受来评估止痛药 在没有癌症生长的情况下，动物模型中的ARTN。为了第三个目标 对抗ARTN阻止癌症和癌症疼痛将通过抗ARTN治疗评估 小鼠异种移植和癌变模型。拟议的研究在 申请人的意见，因为它使用了从口服癌症基因组分析获得的信息到 确定推定的口腔癌促肿瘤基因。这项研究很重要，因为它是 有望为未来的临床试验奠定基础，以评估针对ARTN的实用性 癌症治疗和癌症疼痛的衰减。这项工作将激励识别 额外的促痛性致癌基因，以改善精确的癌症疼痛管理。