Artemin overexpression in oral cancer pain and carcinogenesis

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 有效，但需要剂量递增，副作用降低生活质量。长期 目的是改善口腔癌和口腔癌疼痛的管理。口腔癌疼痛开始 并维持在癌症微环境中。一些过度表达的癌症基因， 癌基因，可以自分泌方式发挥作用，促进癌症和旁分泌方式 as cancer癌症pain疼痛mediators介质.癌症中改变的基因/途径的集合决定了 对治疗的反应，这促使使用针对患者的组合疗法。 个人（精确医学）治疗癌症和疼痛。这一总体目标 应用的目的是确定（a）在口腔癌中过表达的基因artemin（ARTN）是否 是口腔癌癌基因，（B）ARTN是否是口腔癌疼痛介质，和（c）是否 拮抗ARTN可阻止口腔癌并减轻口腔癌疼痛。核心假设是 口腔癌癌基因会促进癌症的发生并引发口腔癌疼痛。的 该项目的基本原理是，可以靶向促痛癌基因来治疗癌症和疼痛。 中心假设将通过追求三个具体目标进行测试：（1）确定ARTN是否是一个 （2）确定ARTN是否是一种癌基因， 伤害感受介质;和（3）确定阻止口腔癌和减轻口腔癌的潜力。 癌症疼痛通过拮抗促痛癌基因。在第一个目标中，ARTN的表达将是 通过免疫组织化学评估完成研究的患者的存档标本， UCSF口腔癌疼痛问卷（UCSFOCPQ），以确定表达是否与 带着痛苦第二个目标是通过操纵ARTN基因来评估ARTN作为癌基因的功能。 在体外培养的细胞和人异种移植小鼠模型中表达。无论ARTN是 疼痛介质将通过测量由操纵以下物质的表达诱导的伤害感受来评估： ARTN在没有癌症生长的动物模型中。第三个目标是， 拮抗ARTN以停止癌症和癌症疼痛将通过以下抗ARTN治疗来评估： 小鼠异种移植和致癌模型。该研究具有创新性， 这是申请人的观点，因为它使用了从口腔癌的基因组分析中获得的信息， 鉴定推定口腔癌促痛癌基因。这项研究意义重大，因为它 预计将为未来的临床试验奠定基础，评估靶向ARTN的效用， 癌症治疗和减轻癌症疼痛。这项工作将促进确定 额外的促痛觉原癌基因，以改善精确的癌症疼痛管理。

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.