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.

抽象的 缺氧是包括乳腺癌在内的实体瘤的主要特征之一，已被证明 与预后不良相关。虽然许多化学治疗剂，例如紫杉醇和 阿霉素在常氧环境中显着有效，它们在低氧肿瘤中的有效性较小 由于输注不良，缺氧和酸度而引起的区域。鉴于其对治疗和肿瘤的重大影响 进展，一种新方法的发展，以专门针对肿瘤的低氧区域 临床需要。为了应对挑战（未满足的医疗需求），我们对此建议的目标是 随着细菌优先迁移并积聚在缺氧的情况下，开发了一种新的益生菌辅助方法 肿瘤区域。我们开发了原始的低氧诱导表达系统，并优化了它的 用于大肠杆菌G3/10细胞，这些细胞已被用作人类的益生菌。我们证明了G3/10 细胞优先将小鼠异种移植乳腺肿瘤的低氧区域定位。有了新工具 在G3/10细胞中缺氧诱导的表达系统，我们将提供杀死癌症的杯赛蛋白， 三阴性乳腺癌的低氧区域中，硫蛋白蛋白或锈酸治疗有限 选择和预后较差。我们假设开发了一种新的细菌辅助方法 在缺氧诱导启动子下表达杀人癌蛋白将提供功能工具 专门针对低氧肿瘤。为了检验我们的假设并改善当前疗法，我们设计了 基于我们的“双向”策略的实验；基于G3/10的治疗与标准的结合 化学治疗剂（紫杉醇和阿霉素），因此化疗会抑制肿瘤 外周区域，灌注肿瘤区域和我们的细菌方法杀死缺氧内部的肿瘤 地区。我们的初步数据强烈支持这一概念。考虑NIH/NCI在 FOA PAR-22-085（基于微生物的癌症成像和治疗 - 作为药物的虫子），我们专门形成了一个 多学科团队将基本，翻译和临床乳腺癌生物学的专业知识整合在一起， 微生物学，分子生物学，免疫学，病理学和生物统计学。有五年的临床前 在本应用中提出的研究，我们将把工程G3/10单元的价值视为有效 细菌辅助功能工具。拟议研究的结果可能会提供新的，并且 有效针对低氧肿瘤微环境的有效治疗策略。