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: 10242843
• 负责人: Donna G Albertson
• 金额: $ 49.06万
• 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/10242843
• 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引起的疼痛。阿片类药物最初