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 疼痛是头颈癌生存的独立程序（HNC）。 高危人乳头瘤病毒（HPV阳性）和 异恋疼痛的发作也可能发出前癌性的信号 癌性转变是疾病的复发，因此疼痛是A 尽管如此，HNC的大量合并症仍缺乏HNC疼痛管理 阿片类药物仍然处于治疗的最前沿。 依赖性依赖性，需要其他疗法来增加HNC疼痛。 现在，实体瘤被广泛接受。 此外，与HPV阳性相比 在AIM 1中，转录在功能上与正常（幼稚）神经元不同。 性别影响肿瘤内神经元的特征和对癌症疼痛的影响 据称，肿瘤发行的小细胞外囊泡（SEV）将神经元吸引到肿瘤床上。 SEV miRNA的初步分析表明这些货物分子直接影响肿瘤神经 此外，我们还表明，HNC的表达会影响AIM中miRNA的包装 2，我们将测试Sev miRNA对体内癌症疼痛的影响。 肿瘤组织，我们在HNC患者肿瘤Slisses中进行了电生理评估。 负肿瘤具有比HPV阳性的明显更高的电活动 该活性可以用止痛药（例如Lidocaine）在AIM 3中衰减。 使用疼痛评估调查表和匹配的患者肿瘤来确定肿瘤电气 活动与患者报告的疼痛相关。 慢速/阻断肿瘤在体内的生长。 肿瘤发行的SEV作为HNC疼痛的关键驱动因素。 可以减弱肿瘤的生长并改善这些发现将支持未来的Clials测试 这些靶标和药物可以控制癌症疼痛。