Hypoxia-activated probiotic agents for breast cancer

用于乳腺癌的缺氧激活益生菌制剂

• 批准号: 10660233
• 负责人: Tohru Yamada
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660233
• 关键词: Acidity; Address; Anaerobic Bacteria; Animal Model; Antineoplastic Agents; Area; Bacteria; Bacterial Proteins; Biodistribution; Biometry; Blinded; Blood flow; Breast Cancer Treatment; Cancer Biology; Cells; Characteristics; Clinical; Data; Development; Doxorubicin; Effectiveness; Engineered Probiotics; Engineering; Environment; Escherichia coli; Exhibits; Experimental Designs; Face; Flagella; Genes; Homing; Human; Hypoxia; Immunology; Induction of Apoptosis; Infusion procedures; Malignant Neoplasms; Mammary Neoplasms; Medical; Microbiology; Molecular Biology; Mus; Neoplasm Metastasis; Outcome; Oxygen; Paclitaxel; Pathology; Perfusion; Pharmaceutical Preparations; Probiotics; Procedures; Prognosis; Proteins; Pseudomonas aeruginosa; Published Comment; Recombinants; Resistance; Risk; Role; Safety; Solid Neoplasm; System; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Transgenic Mice; United States National Institutes of Health; Xenograft procedure; advanced breast cancer; cancer cell; cancer imaging; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; cupredoxin; design; effective therapy; immunogenicity; improved; in vivo; inducible gene expression; malignant breast neoplasm; microbial; migration; multidisciplinary; neoplastic cell; normoxia; novel strategies; opportunistic pathogen; patient derived xenograft model; pre-clinical; pre-clinical research; promoter; selective expression; targeted treatment; therapeutic target; tool; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression

ABSTRACT Hypoxia is one of the main features of solid tumors including breast cancer and has been shown to correlate with a poor prognosis. Although many chemotherapeutic agents such as paclitaxel and doxorubicin are significantly effective in a normoxia environment, they are less effective in hypoxic tumor regions due to poor infusion, hypoxia, and acidity. Given its significant impact on treatment and tumor progression, the development of a new approach to specifically target the hypoxic regions of tumors is clinically needed. To address the challenges (unmet medical needs), our objective for this proposal is to develop a new probiotic-assisted approach as bacteria preferentially migrate and accumulate in the hypoxic region of the tumor. We developed our original hypoxia-inducible expression system and have optimized its use in E. coli G3/10 cells, which have been used as a probiotic in humans. We demonstrated that the G3/10 cells preferentially localized the hypoxic regions of xenografted breast tumors in mice. With the new tools of the hypoxia-inducible expression system in G3/10 cells, we will deliver cancer-killing cupredoxin proteins, azurin or rusticyanin, in the hypoxic region of triple-negative breast cancer as they have limited treatment options and a worse prognosis. We hypothesize that the development of a new bacteria-assisted approach to express cancer-killing proteins under the hypoxia-inducible promoter will provide functional tools for specifically targeting hypoxic tumors. To test our hypothesis and improve current therapy, we designed experiments based on our “bi-directional” strategy; a combination of the G3/10-based therapy with standard chemotherapeutic agents (paclitaxel and doxorubicin), so that the chemotherapy suppresses tumors in the outer periphery regions, perfused tumor regions, and our bacterial approach kills tumor in the hypoxic inner regions. Our preliminary data strongly support this concept. Considering the NIH/NCI’s focusing areas in FOA PAR-22-085 (Microbial-based Cancer Imaging and Therapy - Bugs as Drugs), we specifically formed a multidisciplinary team that integrates expertise in basic, translational, and clinical breast cancer biology, microbiology, molecular biology, immunology, pathology, and biostatistics. With the five years of preclinical research proposed in this application, we will discern the value of engineered G3/10 cells as effective bacteria-assisted functional tools. Results from the proposed studies will potentially provide new and effective treatment strategies that specifically target the hypoxic tumor microenvironment.

摘要 缺氧是包括乳腺癌在内的实体瘤的主要特征之一， 与预后不良有关。尽管许多化学治疗剂如紫杉醇和紫杉醇， 多柔比星在常氧环境中显著有效，它们在缺氧肿瘤中不太有效 由于输液不良、缺氧和酸性，鉴于其对治疗和肿瘤的重大影响， 进展，开发一种新的方法，专门针对肿瘤的缺氧区域， 临床需要。为了应对这些挑战（未满足的医疗需求），我们的提案目标是 开发一种新的益生菌辅助方法，因为细菌优先在缺氧环境中迁移和积累， 肿瘤的区域。我们开发了我们最初的缺氧诱导表达系统，并优化了其表达能力。 在E.大肠杆菌G3/10细胞，已被用作人体益生菌。我们证明了G3/10 细胞优先定位于小鼠异种移植乳腺肿瘤的缺氧区域。随着新的工具， 在G3/10细胞中的低氧诱导表达系统，我们将递送杀死癌症的铜氧还蛋白， 天青蛋白或rusticyanin，在三阴性乳腺癌的缺氧区域，因为它们的治疗有限 选择和更差的预后。我们假设开发一种新的细菌辅助方法 在低氧诱导型启动子下表达癌症杀伤蛋白将提供功能工具， 专门针对缺氧肿瘤。为了验证我们的假设并改善目前的治疗，我们设计了 基于我们的“双向”策略的实验;基于G3/10的治疗与标准治疗的组合 化疗剂（紫杉醇和阿霉素），使得化疗抑制肿瘤中的肿瘤。 外周区域，灌注的肿瘤区域，我们的细菌方法在缺氧的内周区域杀死肿瘤。 地区我们的初步数据强烈支持这一概念。考虑到NIH/NCI的重点领域， FOA PAR-22-085（基于微生物的癌症成像和治疗-作为药物的错误），我们专门成立了一个 多学科团队，整合了基础，转化和临床乳腺癌生物学的专业知识， 微生物学、分子生物学、免疫学、病理学和生物统计学。经过五年的临床前研究， 在这项应用中提出的研究中，我们将识别工程化G3/10细胞的价值， 细菌辅助功能工具。拟议研究的结果将可能提供新的和 有效的治疗策略，专门针对缺氧肿瘤微环境。