Targeting melanoma hypoxia with lactic acid bacterium L. lactis

用乳酸菌 L.lactis 治疗黑色素瘤缺氧

• 批准号: 9451254
• 负责人: Jorge G Gomez-Gutierrez
• 金额: $ 16.75万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-09 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9451254
• 关键词: Affect; Anaerobic Bacteria; Antibiotic Therapy; Area; Attenuated; BRAF gene; Bacteremia; Bacteria; Biodistribution; Blood; Cells; Characteristics; Clinic; Clinical; Clostridium; Color; Communicable Diseases; Consumption; Data; Dermis; Detection; Dose; Dyes; Electromagnetic Energy; Emerging Technologies; Food; Galactose; Galactosidase; Gastrointestinal Diseases; Gene Delivery; Gene Mutation; Gene Targeting; Gene Transfer; Genes; Goals; Home environment; Hybrids; Hypersensitivity; Hypoxia; Image; Immunocompromised Host; Implant; In Vitro; Indocyanine Green; Invaded; LacZ Genes; Lactococcus lactis; Ligands; Light; Listeria; Liver; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Methods; Mind; Modality; Molecular Probes; Mus; Oncogenes; Optics; Organ; Organism; Outcome; Oxygen; PD-1 inhibitors; Pathogenicity; Patients; Penetration; Pharmacotherapy; Photons; Production; Progression-Free Survivals; Proliferating; Reaction; Relapse; Reporter Genes; Resolution; Risk; Salmonella; Sentinel Lymph Node; Signal Transduction; Skin Cancer; Stains; Surface; System; Therapeutic; Time; Tissue Stains; Tissues; Toxicity due to chemotherapy; Translations; Ultrasonics; Virulent; Zinc; absorption; anti-cancer; attenuation; base; beta-Galactosidase; bioluminescence imaging; clinical application; design; experimental study; fluorescence imaging; fluorophore; gene therapy; genetic manipulation; imaging system; improved; in vivo; inhibitor/antagonist; lactic acid bacteria; melanoma; mortality; optoacoustic tomography; outcome forecast; photoacoustic imaging; promoter; routine Bacterial stain; sound; subcutaneous; targeted treatment; therapeutic gene; treatment response; tumor; tumor hypoxia; tumor microenvironment; tumor specificity; tumor-specific gene delivery; uptake

Project Summary Melanoma is the most aggressive form of skin cancer and, if disseminated through the dermis, has a poor prognosis with a high mortality rate. Hypoxia is a component of the tumor microenvironment, which reduces efficacy of both immuno- and chemo-therapies resulting in poor clinical outcome. Therefore, we will exploit the hypoxic microenvironment as a target for gene therapy, utilizing commensal facultative anaerobic bacteria. The overall goal of this proposal is to develop an effective and safe delivery system for cancer gene therapy by targeting the hypoxic tumor microenvironment with food-grade lactic acid bacteria (LAB) Lactococcus lactis (L. lactis). The use of LAB, as opposed to other bacteria, represents a much more desirable strategy to deliver therapeutic genes than attenuated pathogenic strains, as there is no risk of reversion or potential to instigate host reactions in immunocompromised patients. Because identification of tumor-specific accumulation and biodistribution of gene delivery vehicles in vivo is essential for translation of these agents to the clinic, we will utilize a newly emerging technology, multispectral optoacoustic tomography (MSOT). MSOT is a hybrid modality that detects sound waves generated by the absorption of electromagnetic energy, thus enabling the capability for 3D high-resolution at depth and in real time. Our preliminary data indicates that L. lactis expresses high levels of -galactosidase (LacZ), and in combination with 5-bromo-4-chloro-3-indolyl-β-D- galactopyranoside (X-gal), produces a strong blue color to facilitate detection of L. lactis using MSOT. Given these findings, we hypothesize that L. lactis will preferentially colonize the hypoxic areas of the tumor microenvironment to deliver therapeutic genes in a safe, tumor-specific, and effective manner. We propose two aims: (1) Evaluate the efficacy of L. lactis as a gene delivery vehicle in melanoma cells in vitro, and (2) determine the biodistribution and tumor-specific accumulation of L. lactis in metastatic melanoma-bearing mice. The successful completion of this proposal will substantially influence the field of gene therapy, specifically utilization of facultative bacteria as delivery agents for tumor-specific targeting of melanoma.

项目摘要 黑色素瘤是皮肤癌中最具侵袭性的形式，如果通过真皮扩散， 预后不良，死亡率高。缺氧是肿瘤微环境的一个组成部分， 免疫疗法和化学疗法的功效导致不良的临床结果。因此，我们将利用 缺氧微环境作为基因治疗靶点，利用嗜酸性兼性厌氧菌。的 该提案的总体目标是开发一种用于癌症基因治疗的有效和安全的递送系统， 用食品级乳酸菌（LAB）靶向低氧肿瘤微环境乳酸乳球菌（Lactococcus lactis）（L. 乳酸）。与其他细菌相比，使用LAB代表了一种更理想的策略， 治疗基因比减毒致病菌株，因为没有逆转的风险或潜在的煽动 免疫功能低下患者的宿主反应。因为肿瘤特异性积累的鉴定和 基因传递载体在体内的生物分布对于将这些药物转化为临床是必不可少的，我们将 利用一种新兴的技术，多光谱光声层析成像（MSOT）。MSOT是一种混合型 检测通过吸收电磁能量产生的声波的模态，从而使 深度和真实的时间的3D高分辨率能力。我们的初步数据表明，L。lactis 表达高水平的β-半乳糖苷酶（LacZ），并且与5-溴-4-氯-3-吲哚基-β-D- 半乳糖苷（X-gal）产生强蓝色以便于检测L.使用MSOT的乳酸。给定 根据这些发现，我们假设L.乳酸菌将优先定植于肿瘤的缺氧区域 在某些实施例中，微环境可以安全、肿瘤特异性和有效的方式递送治疗基因。我们提出了两 目的：（1）评价L.乳酸作为体外黑素瘤细胞中的基因递送载体，和（2） 测定L.转移性黑色素瘤中的 小鼠该提案的成功完成将对基因治疗领域产生重大影响， 特别是利用兼性细菌作为递送剂用于黑素瘤的肿瘤特异性靶向。

项目成果

Adenovirus Lacking E1b Efficiently Induces Cytopathic Effect in HPV-16-Positive Murine Cancer Cells via Virus Replication and Apoptosis.

缺乏 E1b 的腺病毒通过病毒复制和细胞凋亡有效诱导 HPV-16 阳性鼠癌细胞的细胞病变效应。

• DOI: 10.1080/07357907.2018.1430812
• 发表时间: 2018
• 期刊: Cancer investigation
• 影响因子: 2.4
• 作者: Martinez-Jaramillo,Elvis;Garza-Morales,Rodolfo;Wechman,StephenL;MontesdeOca-Luna,Roberto;Saucedo-Cardenas,Odila;Shirwan,Haval;Yolcu,Esma;McMasters,KellyM;Gomez-Gutierrez,JorgeG
• 通讯作者: Gomez-Gutierrez,JorgeG

Probiotics and Trained Immunity.

• DOI: 10.3390/biom11101402
• 发表时间: 2021-09-24
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Cortes-Perez NG;de Moreno de LeBlanc A;Gomez-Gutierrez JG;LeBlanc JG;Bermúdez-Humarán LG
• 通讯作者: Bermúdez-Humarán LG