Anaerobic Bacteria as Therapeutic Agents for Metastatic Cancer

厌氧细菌作为转移性癌症的治疗剂

基本信息

批准号：
7229908
负责人：
Savio L Woo
金额：
$ 18.76万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229908
关键词：
Alcohol dehydrogenase Anaerobic Bacteria Animals Appearance Area Bacteria Biodistribution Blood Chemical Analysis Body Weight Clinical Clostridium perfringens Colon Carcinoma Colorectal Development Digestive System Disorders Disease Disseminated Malignant Neoplasm Dose End Point Exhibits Facility Construction Funding Category Firefly Luciferases Fluorescence Future Gene Family Genes Genetic Recombination Genomics Green Fluorescent Proteins Growth Hepatobiliary Histology Hypoxia Image Immune In Vitro Inflammatory Invasive Knock-out Laboratories Lead Lesion Life Liver Localized Luciferases Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Modality Monitor Mus Necrosis Normal tissue morphology Nutritional Organ Oxidative Stress Oxygen Pancreas Patients Phospholipase Phospholipase C Rate Recording of previous events Reproduction spores Research Research Personnel Residual state Serum Solid Neoplasm Specificity Superoxide Dismutase System Testing Therapeutic Therapeutic Agents Time Toxic effect Toxin Treatment Efficacy base cytokine gastrointestinal gene therapy glutathione peroxidase improved innovation intravenous administration metastatic colorectal mutant novel novel therapeutics nutrition pancreatic neoplasm programs response time use translational study tumor vector whole body imaging

项目摘要

DESCRIPTION (provided by applicant): As they grow in volume many tumors, including pancreatic and colon cancers, construct poorly vascularized and oxygen-deficient (hypoxic) areas that restrict the access by therapeutic agents and limit the efficacy of currently used anti-cancer modalities. However, the presence of hypoxia also offers the potential for anaerobic bacterial colonization that can lead to tumor destruction. One such anerobic bacterium is Clostridium perfringens (Cp), which contains a major toxin gene that encodes phospholipase C (plc). A plc-deleted strain of Cp (Cp/plc-) has been constructed in our laboratory and shown, after intravenous administration, to colonize and induce massive necrosis in solid tumors in mice. Unfortunately Cp/plc- retains some tolerance to oxygen that enables it to grow in normal tissues at a much reduced rate, and tumor-bearing mice treated with Cp/plc- at the effective doses also exhibited systemic toxicity. We hypothesize that Cp/plc- can be genetically modified to reduce substantially its oxygen tolerance, thereby creating sub-strains that will lead to tumor destruction without toxicity to normal tissues. We propose to delete the superoxide dismutase (sod) gene in a luciferase-expressing strain of Cp/plc-/LUC+ (Cp/plc-/sod-/LUC+). Immune- competent mice with pre-established syngeneic colorectal and pancreatic cancers in the liver will be treated by intravenous administration of Cp/plc-/sod-. Dose response curve and long-term survival at the maximal tolerated dose will be determined. Bacterial biodistribution and intratumoral growth will be determined as a function of time by repeated non-invasive whole-body imaging using luciferrin. Tumor responses in the treated animals will be evaluated by histological examination. Toxicity endpoints will include CBC, blood chemistries, serum proinflammatory cytokine levels and history of major organs. If necessary, additional oxygen tolerance genes can be deleted from Cp/plc-/sod- to further reduce toxicity. We hypothesize that these oxygen-intolerant mutant bacterial sub-strains can be safely applied in tumor-bearing animals, which will selectively localize to, germinate and grow in, and destroy tumors in hypoxic regions. Application of anaerobic bacterial-based vectors is a promising strategy for the development of an effective therapeutic agent that can be administered systemically to treat disseminated solid tumors with hypoxia, and may lead to clinical translational studies in patients with metastatic colorectal and/or pancreatic cancers in the future.

描述（由申请人提供）：随着它们在体积的许多肿瘤中生长，包括胰腺癌和结肠癌，构建了较差的血管化和缺氧（低氧）区域，这些区域限制了治疗剂的进入，并限制了当前使用的抗癌模态的功效。然而，缺氧的存在还为厌氧细菌定殖的潜力提供了可能导致肿瘤破坏的。一种这样的厌氧菌是灌注梭菌（CP），其中包含一个编码磷脂酶C（PLC）的主要毒素基因。在我们的实验室中构建了CP（CP/PLC-）的PLC剥夺菌株，并在静脉内给药后显示，在小鼠的实体瘤中定殖并诱导大量坏死。不幸的是，CP/PLC-保持对氧气的耐受性，使其能够以大大降低的速率在正常组织中生长，而在有效剂量的情况下用CP/PLC-处理的肿瘤小鼠也表现出系统性毒性。我们假设CP/PLC-可以在遗传上修饰以大大降低其氧气耐受性，从而产生会导致肿瘤破坏而不会对正常组织毒性的毒性。我们建议在CP/PLC-/LUC+（CP/PLC-/SOD-/LUC+）的表达荧光素酶菌株中删除超氧化物歧化酶（SOD）基因。通过静脉内给药CP/PLC-/SOD-治疗，具有预先建立的合结直肠癌和胰腺癌的免疫胜任小鼠将接受肝脏中的胰腺癌和胰腺癌。将确定最大耐受剂量下的剂量反应曲线和长期存活。细菌生物分布和肿瘤内生长将通过使用荧光素环的重复非侵入性全身成像来确定时间的函数。治疗动物中的肿瘤反应将通过组织学检查评估。毒性终点将包括CBC，血液化学，血清促炎细胞因子水平和主要器官史。如有必要，可以从CP/PLC-/SOD-中删除额外的氧气耐受基因，以进一步降低毒性。我们假设这些氧气智能突变细菌亚菌株可以安全地应用于荷瘤动物中，这些动物将有选择地定位于低氧区域中的肿瘤，并破坏肿瘤。厌氧细菌基于细菌的载体的应用是开发有效治疗剂的有前途策略，可以系统地给药，以治疗缺氧的传播固体瘤，并且可能会导致转移性结直肠癌和/或胰腺癌症患者的临床翻译研究。