Oral microbiome and inflammatory status in antimicrobially-treated oral cancer patients

接受抗菌药物治疗的口腔癌患者的口腔微生物组和炎症状态

• 批准号: 10685029
• 负责人: Yvonne L Kapila
• 金额: $ 66.41万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-13 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685029
• 关键词: Adjuvant; Adverse event; Alcohol consumption; Anatomy; Animals; Anti-Inflammatory Agents; Apoptosis; Bacteria; Biological; Cancer Patient; Cell Proliferation; Cells; Chronic; Clinical; Clinical Trials; Communities; Complex; Dental Hygiene; Detection; Development; Diet; Dietary intake; Disease; Dose; Elements; Enrollment; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Evolution; Excision; Food Additives; Food Preservatives; Frequencies; Future; Goals; Gram-Positive Bacteria; Growth; Head and Neck Cancer; Heavy Drinking; Homeostasis; Human; Human Microbiome; Human Papilloma Virus Vaccination; Human papilloma virus infection; Immunohistochemistry; Immunotherapy; In Vitro; Incidence; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Investigation; Link; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Mediating; Metastatic/Recurrent; Microbial Biofilms; Mouth Diseases; Nisin; Operative Surgical Procedures; Oral; Oral Characters; Oral Stage; Oral cavity; Organism; Outcome; Participant; Patient-Focused Outcomes; Patients; Periodontal Diseases; Perioperative Adjuvant Therapy; Phase; Population; Prevalence; Progression-Free Survivals; Protozoa; Quantitative Reverse Transcriptase PCR; Radiation therapy; Recurrence; Regimen; Research; Resistance; Risk; Risk Factors; Role; Safety; Saliva; Sampling; Shotguns; Signaling Molecule; Specimen; Structure; Survival Rate; Therapeutic; Tissue-Specific Gene Expression; Tissues; Tobacco use; Toll-like receptors; Treatment Protocols; Virus; anti-cancer; antimicrobial; antitumor effect; bactericide; bacteriocin; base; cancer cell; cancer recurrence; cancer risk; cancer therapy; cancer type; carcinogenesis; carcinogenicity; cell motility; chemokine; cohort; cytokine; demographics; dental biofilm; differential expression; disorder risk; dysbiosis; effective therapy; fungus; head and neck cancer prevention; high risk population; immunoregulation; improved; improved outcome; in vivo; insight; malignant mouth neoplasm; malignant oropharynx neoplasm; metagenomic sequencing; microbial; microbial composition; migration; modifiable risk; mouse model; mouth squamous cell carcinoma; multiple omics; novel; novel therapeutics; oral bacteria; oral microbiome; oral plaque; oral tumorigenesis; pathogen; pathogenic bacteria; primary endpoint; rRNA Genes; response; saliva sample; smoking cessation; targeted treatment; time use; transcriptome sequencing; treatment duration; treatment response; tumor; tumor progression; tumorigenesis; tumorigenic

ABSTRACT The incidence of oral squamous cell carcinoma (OSCC), the most common type of head and neck cancer, continues to rise among numerous demographic groups in the US, yet its 5-year survival rate has not improved for several decades. Despite advances in targeted therapy, immunotherapy and other novel adjuvant regimens, patients with locoregionally advanced and recurrent/metastatic disease continue to have extremely poor outcomes, underscoring the need for more effective treatments for OSCC, which often goes undiagnosed until it has reached late stages. Primary risk factors for OSCC include tobacco use, alcohol consumption, and for oropharyngeal cancers, HPV infection, but cancer incidence is influenced by additional elements such as anatomic site, patient demographics, and likely the individual’s oral microbiome. Given that cases of OSCC are increasing despite targeted head and neck cancer prevention efforts in the US such as smoking cessation and HPV vaccination, there is a strong rationale for exploring other modifiable risk factors that, together with new therapies, can improve outcomes for patients with OSCC as well as other aggressive head and neck cancers. The oral microbiome is a complex and dynamic community of commensal organisms that can become imbalanced (“dysbiotic”) in response to dietary intake, tobacco and alcohol use, and poor dental hygiene. Dysbiosis can pre-dispose an individual to oral disease, including cancer, by enriching for bacterial pathogens that promote carcinogenesis, secrete carcinogenic compounds, and promote chronic inflammation. Thus, reversing oral dysbiosis is a promising approach for protecting against tumorigenesis. The food additive nisin, which is bactericidal against a broad range of pathogens, has been shown to restore oral microbiome diversity, suppress inflammation, and stimulate anti-tumor cellular responses in vitro and in a polymicrobial mouse model of oral cancer, while maintaining its well-established safety profile. However, the potential clinical benefit of nisin for treating OSCC in humans has not been investigated. Here, we propose a Phase I/IIa trial to establish the tolerability and feasibility of administering nisin to OSCC patients who represent high-risk populations. In parallel, we will perform mechanistic studies of nisin and its effects on oral microbiome community structure, inflammasome expression, and anti-cancer cellular responses of the study participants. We will also analyze the emergence of nisin resistance among key oral bacteria, which could provide insight into circumventing nisin resistance in other clinical contexts. We hypothesize that nisin will be well-tolerated among OSCC patients and will counter dysbiosis by inhibiting bacterial pathogen growth and promoting an anti-tumorigenic environment via immunomodulation and anti-cancer cell activity. Our long-term goals are to validate nisin as a promising candidate for OSCC treatment and demonstrate that oral dysbiosis is a major driver of tumorigenesis in humans that can be manipulated, thus highlighting the important yet mostly unrecognized protective role that antimicrobials can exert against cancer in humans.

抽象的 口服鳞状细胞癌（OSCC）的事件是头颈癌最常见的类型， 在美国的许多人口群体中，仍在继续上升，但其5年生存率却没有提高 尽管有针对性的治疗，免疫疗法和其他新型调整方案的进步，但 局部晚期和复发/转移性疾病的患者的患者仍然非常差 结果，强调了对OSCC进行更有效治疗的需求，OSCC通常会无法诊断直到 它已经到达晚期。 OSCC的主要风险因素包括烟草使用，饮酒和 口咽癌，HPV感染，但癌症发病率受其他因素（例如 解剖部位，患者人口统计以及个人的口服微生物组。鉴于OSCC案件是 增加目的地针对性的头颈癌预防措施，例如戒烟和 HPV疫苗接种，探索其他可修改的风险因素有很强的理由 疗法可以改善OSCC以及其他侵略性头颈癌的患者的预后。 口服微生物组是一个复杂而动态的共生生物社区，可以成为 响应饮食摄入，烟草和饮酒以及不良牙齿卫生的反应不平衡（“失调”）。 营养不良可以通过富集细菌病原体来预先介绍一个人，包括癌症，包括癌症 促进致癌，秘密致癌化合物并促进慢性感染。那， 逆转口腔营养不良是预防肿瘤发生的一种有前途的方法。食物添加剂的尼生， 这是针对广泛病原体的杀菌性的，已证明可以恢复口服微生物组的多样性， 抑制注射并刺激体外和多因素小鼠模型的抗肿瘤细胞反应 口腔癌的同时保持其公认的安全性。但是，尼生蛋白的潜在临床益处 尚未研究用于治疗人类OSCC。在这里，我们提出了I/IIA期试验以建立 向代表高风险人群的OSCC患者施用尼我们的耐药性和可行性。并联， 我们将对Nisin及其对口腔微生物组社区结构的影响进行机械研究， 研究参与者的炎性体表达和抗癌细胞反应。我们还将分析 关键口腔细菌之间耐药性的出现，这可以提供洞察力的奈辛蛋白 在其他临床环境中的抵抗。我们假设Nisin将在OSCC患者中得到良好的耐受性和 将通过抑制细菌病原体生长并通过 免疫调节和抗癌细胞活性。我们的长期目标是验证尼生作为承诺 OSCC治疗的候选者，并证明口腔失调是人类肿瘤发生的主要驱动力 可以操纵的，从而强调了重要但主要未识别的保护作用 抗菌素可以在人类中施加针对癌症。