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

基本信息

  • 批准号:
    10642765
  • 负责人:
  • 金额:
    $ 61.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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。与此同时, 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尼生素作为一种有前途的药物 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

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 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
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Yvonne L Kapila其他文献

Poor oral health and inflammatory, haemostatic and cardiac biomarkers in older age: Results from two studies in the UK and USA.
老年人口腔健康状况不佳以及炎症、止血和心脏生物标志物:英国和美国两项研究的结果。

Yvonne L Kapila的其他文献

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{{ truncateString('Yvonne L Kapila', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 61.52万
  • 项目类别:
UCLA Dental Specialty and Ph.D. Program
加州大学洛杉矶分校牙科专业和博士学位
  • 批准号:
    10466831
  • 财政年份:
    2018
  • 资助金额:
    $ 61.52万
  • 项目类别:
UCLA Dental Specialty PhD Program
加州大学洛杉矶分校牙科专业博士课​​程
  • 批准号:
    10662146
  • 财政年份:
    2018
  • 资助金额:
    $ 61.52万
  • 项目类别:
Biomarkers of Aggressive Oral Cancer
侵袭性口腔癌的生物标志物
  • 批准号:
    8739641
  • 财政年份:
    2013
  • 资助金额:
    $ 61.52万
  • 项目类别:
Apoptosis Regulated by Fibronectin Signaling Pathways
纤连蛋白信号通路调控细胞凋亡
  • 批准号:
    7654373
  • 财政年份:
    2008
  • 资助金额:
    $ 61.52万
  • 项目类别:
APOPTOTIC BIOMARKERS OF PERIODONTAL DISEASE
牙周疾病的细胞凋亡生物标志物
  • 批准号:
    7603835
  • 财政年份:
    2007
  • 资助金额:
    $ 61.52万
  • 项目类别:
Apoptosis Regulated by Fibronectin Signaling Pathways
纤连蛋白信号通路调控细胞凋亡
  • 批准号:
    7340263
  • 财政年份:
    2006
  • 资助金额:
    $ 61.52万
  • 项目类别:
FIBRONECTIN REGULATION OF CARCINOMA APOPTOSIS
纤连蛋白对癌细胞凋亡的调节
  • 批准号:
    7066044
  • 财政年份:
    2004
  • 资助金额:
    $ 61.52万
  • 项目类别:
PILOT--INVASION REGULATED BY FIBRONECTIN AND RECEPTORS
飞行员——由纤连蛋白和受体调节的入侵
  • 批准号:
    6893685
  • 财政年份:
    2004
  • 资助金额:
    $ 61.52万
  • 项目类别:
FIBRONECTIN REGULATION OF CARCINOMA APOPTOSIS
纤连蛋白对癌细胞凋亡的调节
  • 批准号:
    7934164
  • 财政年份:
    2004
  • 资助金额:
    $ 61.52万
  • 项目类别:

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