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: 10642765
• 负责人: Yvonne L Kapila
• 金额: $ 61.52万
• 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/10642765
• 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; Genetic Transcription; 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; Proliferating; Protozoa; Quantitative Reverse Transcriptase PCR; Radiation therapy; Recurrence; Recurrent Malignant Neoplasm; 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; cancer cell; cancer recurrence; cancer risk; cancer therapy; cancer type; carcinogenesis; carcinogenicity; cell motility; chemokine; cohort; cytokine; demographics; dental biofilm; differential expression; 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; phase I/IIa trial; 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.

摘要 口腔鳞状细胞癌（OSCC）是头颈部最常见的癌症类型， 在美国的许多人口统计学群体中持续上升，但其5年生存率并未提高 几十年了尽管靶向治疗、免疫治疗和其他新的辅助治疗方案取得了进展， 局部晚期和复发/转移性疾病的患者仍然具有极差的 结果，强调需要更有效的治疗口腔鳞状细胞癌，这往往无法诊断，直到 已经到了后期。口腔鳞状细胞癌的主要危险因素包括吸烟，饮酒， 口咽癌，HPV感染，但癌症的发病率受到其他因素的影响，如 解剖部位、患者人口统计学以及可能的个体的口腔微生物组。由于口腔鳞状细胞癌的病例是 尽管在美国有针对性的头颈癌预防工作，如戒烟， HPV疫苗接种后，探索其他可改变的风险因素有很强的理由， 治疗，可以改善OSCC以及其他侵袭性头颈癌患者的预后。 口腔微生物组是一个复杂而动态的口腔微生物群落， 不平衡（“生态失调”）的饮食摄入，烟草和酒精的使用，以及不良的牙齿卫生。 通过富集细菌病原体，生态失调可使个体易患口腔疾病，包括癌症 其促进致癌作用、分泌致癌化合物并促进慢性炎症。因此，在本发明中， 逆转口腔生态失调是预防肿瘤发生的有希望的方法。食品添加剂乳酸链球菌素， 其对广泛的病原体具有杀菌作用，已经显示出恢复口腔微生物组多样性， 在体外和多微生物小鼠模型中抑制炎症和刺激抗肿瘤细胞应答 口腔癌，同时保持其良好的安全性。然而，乳链菌肽的潜在临床益处 用于治疗人类口腔鳞状细胞癌的方法尚未研究。在这里，我们提出了一个I/IIa期试验，以建立 对代表高危人群的OSCC患者给予乳链菌肽的耐受性和可行性。同时， 我们将进行乳链菌肽的机制研究及其对口腔微生物群落结构的影响， 炎性体表达和研究参与者的抗癌细胞反应。我们还将分析 关键口腔细菌中出现乳链菌肽耐药性，这可以为规避乳链菌肽提供见解 其他临床环境中的耐药性。我们假设乳链菌肽在口腔鳞状细胞癌患者中耐受性良好， 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， 免疫调节和抗癌细胞活性。我们的长期目标是验证乳链菌肽作为一种有前途的 OSCC治疗的候选人，并证明口腔生态失调是人类肿瘤发生的主要驱动因素 这是可以被操纵的，因此突出了重要但大多数未被认识到的保护作用， 抗菌剂可以对抗人类的癌症。

项目成果

Specific Oral Microbial Differences in Proteobacteria and Bacteroidetes Are Associated with Distinct Sites When Moving from Healthy Mucosa to Oral Dysplasia-A Microbiome and Gene Profiling Study and Focused Review.

• DOI: 10.3390/microorganisms11092250
• 发表时间: 2023-09-07
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Radaic A;Shamir ER;Jones K;Villa A;Garud NR;Tward AD;Kamarajan P;Kapila YL
• 通讯作者: Kapila YL