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.

项目总结/摘要 疼痛是头颈癌（HNC）生存的独立预后因素。这些癌症可能是 大致分为由高危人乳头瘤病毒（HPV阳性）感染引起的那些， 那些是突变驱动的（HPV阴性）。口面部疼痛的发作可能是癌前病变的信号， 癌症的转变以及疾病的复发，这表明了预测价值。因此，疼痛是一种 HNC中的显著共病。尽管如此，HNC疼痛管理缺乏完善的指南 阿片类药物仍然是治疗的前沿。考虑到它对病人生存的影响和广泛的风险 由于阿片类药物依赖，需要额外的治疗来解决HNC疼痛。体内神经元的存在 实体瘤现在被广泛接受。我们的初步数据显示，HPV阴性肿瘤明显多于 比HPV阳性的人更容易感染。此外，我们发现肿瘤内神经元是 在转录和功能上不同于正常（幼稚）神经元。在目标1中，我们将测试HPV状态 和性别影响肿瘤内神经元的这些特征及其对癌症疼痛的影响。我们有 先前发表的肿瘤释放的小细胞外囊泡（sEV）引诱神经元到肿瘤床。我们 对sEV miRNAs的初步分析表明，这些货物分子直接影响肿瘤神经支配。在 此外，我们还发现HNC癌基因的表达影响了sEV中miRNA的包装。在Aim中 2、我们将在体内测试sEV miRNAs对癌症疼痛的影响。此外，考虑到神经元的存在 在HNC患者肿瘤切片中，我们电生理学地评估了活性。我们发现HPV 阴性肿瘤比HPV阳性肿瘤具有显著更高的电活性。我们还表明 这种活性可以用疼痛靶向药物（例如利多卡因）来抑制。在目标3中，我们 使用疼痛评估患者问卷和匹配的患者肿瘤来确定是否存在肿瘤电刺激。 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， 减缓/阻断体内肿瘤生长。总之，这些研究的结果将确定肿瘤内神经元 和肿瘤释放的sEV作为HNC疼痛的关键驱动因素。此外，我们将确定神经靶向药物， 可以抑制肿瘤生长提高存活率这些发现将支持未来的临床试验测试 这些目标和药物用于控制癌症疼痛。