Anaerobic Bacteria as Oncopathic Agents for Pancreatic Cancer

厌氧细菌作为胰腺癌的致癌剂

• 批准号: 7651591
• 负责人: Savio L Woo
• 金额: $ 35.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651591
• 关键词: Alcohol dehydrogenase; Anaerobic Bacteria; Animals; Attenuated; Bacteria; Bacterial Spores; Blood Vessels; Blood flow; Cancer Etiology; Cell membrane; Cells; Cessation of life; Clostridium perfringens; Combination Drug Therapy; Combined Modality Therapy; Complement; Cytotoxic agent; Development; Dose; Exhibits; Family member; Future; Gas Gangrene; Genes; Germination; Growth; Hypoxia; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intravenous infusion procedures; Knock-in Mouse; Knock-out; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Microbe; Modality; Modeling; Mus; Neoplasms in Vascular Tissue; Normal tissue morphology; Outcome; Oxygen; Panton-Valentine leukocidin; Patients; Phagocytes; Pharmaceutical Preparations; Phospholipase; Phospholipase C; Property; Radiation therapy; Recombinants; Refractory; Relapse; Reproduction spores; Residual state; Safety; Solid Neoplasm; Staphylococcus aureus; Superoxide Dismutase; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Treatment Efficacy; Treatment outcome; Virulence Factors; Woman; Yersinia enterocolitica; alpha Toxin; bactericide; cancer therapy; chemotherapeutic agent; chemotherapy; glutathione peroxidase; improved; in vivo; intravenous administration; men; mouse model; mutant; neoplastic cell; novel; novel therapeutics; public health relevance; response; standard of care; tumor

DESCRIPTION (provided by applicant): A major challenge in cancer therapy has been the selective and efficient delivery of therapeutic agents to the lesions. Solid tumors such as pancreatic cancer often have poorly-vascularized regions at their cores that are hypoxic and are not readily accessible to the vascular delivery of chemotherapeutic drugs. Hypoxia, however, offers the potential for anaerobic bacterial colonization that can lead to tumor destruction, and one such anaerobic bacterium is Clostridium perfringens (Cp). We have deleted its alpha toxin gene that encodes phospholipase c (Cp/plc-), and showed that the mutant strain can no longer cause gas gangrene in mice. We have also showed that the dormant spores of this deletion mutant, when administered intravenously in mice bearing an orthotopic model of pancreatic cancer, were capable of germination and proliferation in the hypoxic tumor regions with oncopathic effects. However, Cp/plc- does have residual tolerance to oxygen and retains limited capabilities for growth in oxygenated tissues, leading to significant toxicities in animals when administered intravenously at high doses. Superoxide dismutase (sod) is a major oxygen tolerance gene that has also been knocked out in Cp/plc-. The maximum tolerated dose of this knock-out strain (Cp/plc-/sod-) was elevated by one-log over that of Cp/plc- in tumor-bearing mice. To further improve safety, we hypothesize that sequential knock-out of the other major oxygen tolerance genes in the sod knock-out strain will produce an oxygen-intolerant strain (oiCp/plc-) with maximal tumor selectivity and minimal toxicity. However, intratumoral bacteria replication was inhibited by a rapid accumulation of host inflammatory cells that are bactericidal, which limited the extent of tumor response. To enhance oncopathic potency, we hypothesize that intratumoral replication of oiCp/plc- and its antitumor efficacy can be substantially elevated by constructing recombinants that express inflammation suppressive genes from heterologous microbes endowed naturally with such properties. These novel recombinant strains will have maximal tumor selectivity and oncopathic potency in poorly-vascularized tumors. Finally, most solid tumors also contain regions that are relatively well-vascularized and oxygenated, and hence refractory to the anaerobic bacteria treatment. These vascularized and oxygenated regions however, are susceptible to systemically administered chemotherapeutic drugs. Thus we hypothesize that anaerobic bacteria treatment that targets the hypoxic cores of the poorly- vascularized tumors will be complementary to systemic chemotherapy that targets the vascularized regions, leading to substantially enhanced tumor destruction and survival prolongation. Successful conduct of the proposed studies may lead to the development of recombinant Cp spores as a novel class of therapeutic agents that can be administered systemically and safely to patients with advanced pancreatic cancer and other poorly-vascular tumors in the future and which, in combination with chemotherapy, may lead to improved treatment outcome than systemic chemotherapy alone, which is the standard of care at present. PUBLIC HEALTH RELEVANCE: Although pancreatic cancer is only the 10th and 11th leading cause of new cancer cases in U.S. men and women, respectively, it is the 4th leading cause of cancer deaths for both U.S. men and women. 33,370 deaths and 37,170 new cases are estimated for 2007 in the U.S. alone. Currently available treatment modalities include chemotherapy and radiation therapy, which are not particularly effective for pancreatic cancer. Anaerobic bacteria can target the hypoxic cores in tumors that will be complementary to chemotherapy, such that the outcome of combination treatment will be superior to chemotherapy alone.

描述（由申请人提供）：癌症治疗的主要挑战是将治疗剂的选择性和有效递送到病变中。胰腺癌等实体瘤在其核心的血管性区域通常很差，而核心则缺氧，并且不容易获得化学治疗药物的血管递送。然而，缺氧为可能导致肿瘤破坏的厌氧细菌定植提供了潜力，一种这种厌氧细菌是灌注梭状芽胞杆菌（CP）。我们删除了其编码磷脂酶C（CP/PLC-）的α毒素基因，并表明突变菌株无法再引起小鼠的气体坏疽。我们还表明，这种缺失突变体的休眠孢子在带有胰腺癌原位模型的小鼠静脉内给药时，能够在具有肿瘤效应的低氧肿瘤区域发芽和增殖。但是，CP/PLC-确实具有对氧气的残留耐受性，并保留有限的氧化组织生长能力，当以高剂量静脉注射时会导致动物的明显毒性。超氧化物歧化酶（SOD）是一种主要的氧耐受基因，也已在CP/PLC-中被淘汰。该基因敲除应变（CP/PLC-/SOD-）的最大耐受剂量被一室升高的肿瘤小鼠中的CP/PLC-的最大耐受剂量升高。为了进一步提高安全性，我们假设在SOD敲除菌株中其他主要氧气耐受基因的顺序敲除将产生具有最大肿瘤选择性和最小毒性的氧气智能菌株（OICP/PLC-）。然而，肿瘤内细菌的复制受到造成杀菌性的宿主炎症细胞的迅速积累，从而限制了肿瘤反应的程度。为了提高癌性效力，我们假设可以通过构造表达来自异源微生物抑制炎症基因的重组因子来显着提高OICP/PLC-及其抗肿瘤功效的肿瘤内复制及其抗肿瘤功效。这些新型的重组菌株将在血管性较差的肿瘤中具有最大的肿瘤选择性和肿瘤性效力。最后，大多数实体瘤还包含相对良好的血管化和氧化的区域，因此对厌氧细菌的治疗难治性。但是，这些血管化和含氧区域易受系统施用的化学治疗药物的影响。因此，我们假设靶向靶向较差血管化肿瘤低氧核心的厌氧菌治疗将与靶向血管化区域的全身化疗相辅相成，从而大大增加了肿瘤破坏和生存延长。拟议研究的成功进行的成功可能导致重组CP孢子作为一种新型的治疗剂，可以系统地和安全地对患有晚期胰腺癌和其他不良血管肿瘤的患者进行安全和安全的治疗，并且与化学疗法结合使用，可以与全身化学疗法相比，与单独的化学疗法相比，这是单独的治疗结果。公共卫生相关性：尽管胰腺癌仅是美国男性和女性新癌症病例的第十和第11个主要原因，但这是美国男性和女性癌症死亡的第四个主要原因。仅在美国，估计2007年估计33,370例死亡和37,170例新病例。目前可用的治疗方式包括化学疗法和放射治疗，这对胰腺癌并不特别有效。厌氧细菌可以靶向肿瘤中的低氧核心，这些核心将与化学疗法相辅相成，从而使联合治疗的结果仅优于化学疗法。