Intra-tumoral neurons contribute to head and neck cancer pain

肿瘤内神经元导致头颈癌疼痛

• 批准号: 10635591
• 负责人: Paola Drapkin Vermeer
• 金额: $ 47.87万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635591
• 关键词: Address; Afferent Neurons; Alcohols; Animals; Attenuated; Beds; Biological Assay; C57BL/6 Mouse; CCND1 gene; Cancer Control; Cancer Pain Management; Cancer cell line; Cancerous; Cell Line; Characteristics; Clinical Trials; Data; Disease; Disease Progression; Drug Controls; Drug Targeting; Early Intervention; Electrophysiology (science); Face; Female; Future; Genetic Transcription; Growth; Guidelines; HPV-High Risk; Head and Neck Cancer; Human Papillomavirus; Implant; In Vitro; Infection; Injections; Lidocaine; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Mus; Mutation; Nerve; Neurites; Neurons; Nociceptors; Oncogenes; Opiate Addiction; Opioid; Oral; Orofacial Pain; Outcome Study; Pain; Pain Measurement; Pain management; Papillomavirus Infections; Pathway interactions; Patients; Pharmaceutical Preparations; Predictive Value; Prognostic Factor; Publishing; Questionnaires; Recurrent disease; Reporting; Risk; Sampling; Screening procedure; Sensory; Severities; Signal Transduction; Slice; Smoking; Solid Neoplasm; Stimulus; TRPV1 gene; Testing; Time; Toxic Environmental Substances; Tracer; Transgenic Animals; Transgenic Mice; Tumor Promotion; Tumor Tissue; cancer pain; cancer survival; carcinogenesis; cell type; comorbidity; defined contribution; experimental study; extracellular vesicles; head and neck cancer patient; implantation; improved; in vitro activity; in vivo; in vivo evaluation; male; nerve supply; overexpression; pharmacologic; premalignant; recruit; response; sex; stable cell line; transcriptome sequencing; tumor; tumor growth; vesicular release

Project Summary/Abstract Pain is an independent prognostic factor for survival in head and neck cancer (HNC). These cancers can be broadly divided into those that are induced by infection with high-risk human papillomavirus (HPV positive) and those that are mutationally driven (HPV negative). The onset of orofacial pain may signal the pre-cancerous to cancerous transition as well as the recurrence of disease, suggesting a predictive value. Thus, pain is a significant co-morbidity in HNC. Despite this, well-established guidelines for HNC pain management are lacking and opioids remain at the forefront of treatment. Given its influence on patient survival and the widespread risk of opioid dependence, additional therapies are needed to address HNC pain. The presence of neurons within solid tumors is now widely accepted. Our preliminary data show that HPV negative tumors are significantly more innervated than their HPV positive counterparts. Moreover, we show that intra-tumoral neurons are transcriptionally and functionally different from normal (naïve) neurons. In Aim 1, we will test how HPV status and sex influence these characteristics of intra-tumoral neurons and their effects on cancer pain. We have previously published that tumor-released small extracellular vesicles (sEVs) lure neurons to the tumor bed. Our preliminary analysis of sEV miRNAs suggest that these cargo molecules directly impact tumor innervation. In addition, we also show that expression of HNC oncogenes influences the packaging of miRNAs in sEVs. In Aim 2, we will test the effect of sEV miRNAs on cancer pain in vivo. In addition, given the presence of neurons within tumor tissues, we electrophysiologically assessed activity in HNC patient tumor slices. We found that HPV negative tumors harbor a significantly higher electrical activity than those that are HPV positive. We also show that this activity can be pharmacologically attenuated with pain-targeting drugs (e.g. lidocaine). In Aim 3, we will use a pain assessment patient questionnaire and matched patient tumors to determine whether tumoral electrical activity correlates with patient reported pain. We will also test whether drugs that attenuate pain also function to slow/block tumor growth in vivo. Together, the outcomes of these studies will define that intra-tumoral neurons and tumor-released sEVs as critical drivers of HNC pain. Moreover, we will have identified nerve targeting drugs that can attenuate tumor growth and improve survival. These findings will support future clinical trials testing these targets and drugs for the control of cancer pain.

项目摘要/摘要 疼痛是头颈癌（HNC）生存的独立预后因素。这些癌症可以是 大致分为那些因高风险人乳头瘤病毒（HPV阳性）感染而诱导的。 那些是突变驱动的（HPV负）。口面疼痛的发作可能会表明前癌症 癌性过渡以及疾病的复发，表明预测价值。那是痛苦 HNC中的显着合并症。尽管如此，缺乏公认的HNC疼痛管理指南 阿片类药物仍然处于治疗的最前沿。鉴于它对患者生存和宽度风险的影响 阿片类药物依赖性，需要其他疗法来解决HNC疼痛。内在神经元的存在 实体瘤现在已被广泛接受。我们的初步数据表明，HPV阴性肿瘤明显更多 比其HPV阳性对应物的支配。此外，我们表明肿瘤内神经元是 在转录和功能上与正常（幼稚）神经元不同。在AIM 1中，我们将测试HPV状态 性别影响着肿瘤内神经元的这些特征及其对癌症疼痛的影响。我们有 先前发表的说，肿瘤释放的小细胞外蔬菜（SEV）将神经元吸引到肿瘤床上。我们的 SEV miRNA的初步分析表明，这些货物分子直接影响肿瘤神经。在 此外，我们还表明，HNC癌基因的表达会影响miRNA在SEV中的包装。目标 2，我们将测试SEV miRNA对体内癌症疼痛的影响。另外，鉴于内部神经元的存在 肿瘤组织，我们通过电生理评估了HNC患者肿瘤切片中的活性。我们发现HPV 阴性肿瘤具有比HPV阳性的肿瘤明显更高。我们也显示 可以用靶向止痛药（例如利多卡因）衰减这种活性。在AIM 3中，我们将 使用疼痛评估患者问卷调查并匹配患者肿瘤以确定肿瘤电气是否是否 活动与患者报告的疼痛相关。我们还将测试减轻疼痛的药物是否也起作用 缓慢/阻断体内肿瘤的生长。总之，这些研究的结果将定义肿瘤内神经元 肿瘤发行的SEV是HNC疼痛的关键驱动因素。此外，我们将确定靶向药物的神经 这可以减轻肿瘤的生长并改善生存率。这些发现将支持未来的临床试验测试 这些靶标和药物可以控制癌症疼痛。