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）：随着许多肿瘤（包括胰腺癌和结肠癌）体积的增大，会形成血管化不良和缺氧（缺氧）的区域，从而限制了治疗药物的进入并限制了当前使用的抗癌方式的功效。然而，缺氧的存在也提供了厌氧细菌定植的可能性，从而导致肿瘤破坏。产气荚膜梭菌 (Cp) 就是这样一种厌氧细菌，它含有编码磷脂酶 C (plc) 的主要毒素基因。我们的实验室构建了 plc 缺失型 Cp 菌株 (Cp/plc-)，经静脉注射后，可在小鼠实体瘤中定植并诱导大量坏死。不幸的是，Cp/plc- 保留了一定的氧耐受性，使其在正常组织中的生长速度大大降低，并且用有效剂量的 Cp/plc- 治疗的荷瘤小鼠也表现出全身毒性。我们假设 Cp/plc- 可以通过基因改造来大幅降低其氧耐受性，从而产生能够破坏肿瘤而不对正常组织产生毒性的亚菌株。我们建议删除荧光素酶表达菌株 Cp/plc-/LUC+ (Cp/plc-/sod-/LUC+) 中的超氧化物歧化酶 (sod) 基因。将通过静脉内施用Cp/plc-/sod-来治疗肝脏中预先确定的同基因结直肠癌和胰腺癌的免疫活性小鼠。将确定最大耐受剂量下的剂量反应曲线和长期存活率。通过使用荧光素的重复非侵入性全身成像，将确定细菌生物分布和瘤内生长作为时间的函数。将通过组织学检查评估治疗动物的肿瘤反应。毒性终点包括全血细胞计数、血液化学、血清促炎细胞因子水平和主要器官病史。如有必要，可以从 Cp/plc-/sod- 中删除额外的耐氧基因，以进一步降低毒性。我们假设这些不耐氧的突变细菌亚菌株可以安全地应用于荷瘤动物，它们将选择性地定位于缺氧区域、在缺氧区域发芽、生长并摧毁肿瘤。应用基于厌氧细菌的载体是开发有效治疗剂的一种有前途的策略，该治疗剂可以全身给药以治疗缺氧的播散性实体瘤，并可能导致转移性结直肠癌和/或胰腺癌患者的临床转化研究。未来。