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 口腔鳞状细胞癌（OSCC）是最常见的头颈癌类型，其发病率 美国众多人口群体中的死亡率持续上升，但其5年生存率并未提高 尽管靶向治疗、免疫治疗和其他新型辅助疗法取得了进展， 患有局部晚期和复发/转移性疾病的患者仍然状况极差 的结果，强调需要更有效的 OSCC 治疗方法，这种疾病往往直到 OSCC 的主要危险因素包括吸烟、饮酒和吸烟。 口咽癌、HPV 感染，但癌症发病率还受到其他因素的影响，例如 鉴于 OSCC 病例的解剖部位、患者人口统计数据以及可能的个人口腔微生物组。 尽管美国采取了有针对性的头颈癌预防措施，例如戒烟和 HPV 疫苗接种，有充分理由探索其他可改变的风险因素，连同新的 疗法可以改善 OSCC 以及其他侵袭性头颈癌患者的预后。 口腔微生物群是一个复杂而动态的共生生物群落，可以成为 由于饮食摄入、吸烟和饮酒以及牙齿卫生不良而导致的不平衡（“生态失调”）。 菌群失调可以通过富集细菌病原体而使个体预先罹患口腔疾病，包括癌症 促进致癌作用，分泌致癌化合物，并促进慢性炎症。 逆转口腔生态失调是预防肿瘤发生的一种有前途的方法。 它对多种病原体具有杀菌作用，已被证明可以恢复口腔微生物组的多样性， 在体外和多种微生物小鼠模型中抑制炎症并刺激抗肿瘤细胞反应 口腔癌的治疗，同时保持其完善的安全性，但是乳链菌肽的潜在临床益处。 在此，我们建议进行 I/IIa 期试验来确定治疗人类 OSCC 的效果。 同时，对代表高危人群的 OSCC 患者施用乳链菌肽的耐受性和可行性。 我们将对乳链菌肽及其对口腔微生物群落结构的影响进行机制研究， 我们还将分析研究参与者的炎症体表达和抗癌细胞反应。 关键口腔细菌中出现了乳链菌肽耐药性，这可以为规避乳链菌肽提供见解 我们相信乳链菌肽在 OSCC 患者中具有良好的耐受性。 将通过抑制细菌病原体生长和促进抗肿瘤环境来对抗生态失调 我们的长期目标是验证乳链菌肽是一种有前途的药物。 OSCC 治疗的候选者，并证明口腔生态失调是人类肿瘤发生的主要驱动因素 可以被操纵，从而凸显了重要但大多未被认识到的保护作用 抗菌药物可以对抗人类癌症。