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 黑色素瘤是皮肤癌最具侵略性的形式，如果通过真皮传播， 预后高死亡率。缺氧是肿瘤微环境的组成部分，可减少 免疫和化学治疗的功效导致临床结果不佳。因此，我们将利用 低氧微环境作为基因治疗的靶标，使用共生疗法厌氧菌。 该提案的总体目标是通过通过 用食物级乳酸菌（LAB）乳酸菌靶向低氧肿瘤微环境（L. 乳酸）。与其他细菌相反，实验室的使用代表了交付的一种更理想的策略 治疗基因比致病性菌株减弱，因为没有反向或潜力的风险 免疫功能低下的患者的宿主反应。因为鉴定肿瘤特异性积累和 体内基因输送车的生物分布对于将这些药物转换为诊所至关重要，我们将 利用新兴技术，多光谱光声断层扫描（MSOT）。 MSOT是一种混合动力 检测到通过电子能量的抽象产生的声波的模态，从而使 在深度和实时进行3D高分辨率的能力。我们的初步数据表明乳酸乳乳杆菌 表达高水平的 - 半乳糖苷酶（LACZ），并与5-溴-4-氯-3- indolyl-β-D-结合使用 半乳糖酸（X-GAL）产生强蓝色，以使用MSOT促进乳酸乳杆菌的检测。给出 这些发现，我们假设乳酸乳乳果会优先定居肿瘤的低氧区域 微环境以安全，肿瘤特异性和有效方式传递热基因。我们提出了两个 目的：（1）评估乳酸乳杆菌作为在体外黑色素瘤细胞中的基因递送载体的效率，（2） 确定乳酸乳杆菌在转移性黑色素瘤中的生物分布和肿瘤特异性积累 老鼠。该提案的成功完成将大大影响基因治疗领域， 特别利用兼性细菌作为肿瘤特异性靶向黑色素瘤的递送剂。

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