Tumor-targeting Salmonella expressing apoptosis-inducing cytotoxic proteins

表达细胞凋亡诱导细胞毒性蛋白的肿瘤靶向沙门氏菌

基本信息

批准号：
8660303
负责人：
DAVID G BERMUDES
金额：
$ 10.88万
依托单位：
CALIFORNIA STATE UNIVERSITY NORTHRIDGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-10 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660303
关键词：
Admission activity Algorithms Antineoplastic Agents Apoptosis Attenuated Bacteria Biology Breast Carcinoma Breast Epithelial Cells C-terminal CCL7 gene Cancerous Cell Cycle Arrest Cells Chimera organism Chimeric Proteins Clinical Research Clinical Trials Combination Drug Therapy Combined Modality Therapy Cultured Tumor Cells Cytotoxin DNA chemical synthesis Data Disease Distant Dose Drug Delivery Systems Educational process of instructing Engineering Enrollment Epitopes Filipino Funding Future Generations Genes Genetic Engineering Grant Hispanics Human In Vitro Individual Injection of therapeutic agent Intracellular Transport Koreans Laboratories Ligands M cell MCF7 cell Malignant Epithelial Cell Malignant Neoplasms Master&apos s Degree Microbiology Molecular Target Normal Cell Normal tissue morphology Nuclear Localization Signal Patients Peptides Production Proteins Recruitment Activity Relative (related person)Research Research Training Safety Salmonella Schools Site Solid Neoplasm Specificity Students System Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Tumor Cell Line Viral Proteins Work attenuation base cancer cell cancer therapy cell type cost cytolethal distending toxin cytotoxic cytotoxicity design graduate student in vivo indexing killings mutant neoplastic cell novel polypeptide programs public health relevance research study synthetic biology synthetic construct synthetic protein therapeutic protein tumor tumor specificity vector

项目摘要

DESCRIPTION (provided by applicant): Tumor-targeting bacteria offer a number of advantages over other cancer drug delivery systems, including targeting of multiple tumors from a distant inoculation site, selective intratumoral replication, a high degree of attenuation and safety, and the ability to express anti-cancer proteins directly within the tumor. Remarkably, attenuated Salmonella localize within solid tumors at levels at least 1000 times greater than other tissues. Human clinical studies have validated the safety of intravenously administered attenuated bacterial mutants, established tolerated multiple doses, and have shown that tumor targeting occurs in some patients. However, no anti-tumor activity was observed, even in patients in which the Salmonella were verified to have colonized their tumors. We hypothesize that the lack of antitumor efficacy in the human clinical trials can be overcome by engineering apoptosis (programmed cell death) -inducing cytotoxic proteins that are able to kill tumor cells. The Specific Aims are designed to test individual proteins and protein combinations in order to develop tumor-targeted Salmonella vectors with enhanced antitumor activity. The project utilizes synthetic biology, the chemical synthesis of DNA, to construct genes encoding proteins that will kill cancer cells. The composition of these synthetic proteins is based on combinations of known cancer-killing and cancer-targeting protein components, which, when combined, result in proteins with the selective ability to kill cancer. A preliminary study of novel bifunctional fusios of the apoptosis and cytotoxic polypeptides will also be conducted in order to combine aspects of their cell targeting, subcellular transport and intracellular molecular targets as a means to confer enhanced potency together with tumor specificity, and to generate preliminary data for a new grant submission. The bacteria described here are highly safe and suitable for students to work on in the lab. Students are recruited from the microbiology courses the PI teaches and integrates his research on tumor-targeted Salmonella. Students are also recruited from the Graduate School Admission Program, and the MARC and RISE programs at CSUN. Although the PI has only been at CSUN for 1.5 years, he has already provided laboratory-based research training for 11 students, including 3 Hispanics, 2 Armenians, 2 Indians, 1 Filipino, 1 Thai, and 1 Korean. The project is expected to involve two graduate students seeking their Masters Degree over a two to three year period, with a total of up to four graduate students during the funding period, and one to two directed research undergraduates per year; up to eight during the course of the funding period, as well as one to two students per semester enrolled in the Biology research course, for a total of between 14 and 28 students during the funding period.

描述（由申请人提供）：涉及肿瘤的细菌比其他癌症药物输送系统具有许多优势，包括靶向远处接种部位的多个肿瘤，选择性肿瘤内复制，高度衰减和安全性以及能够直接在肿瘤内表达抗癌蛋白。值得注意的是，减弱的沙门氏菌位于实体瘤中，其水平至少比其他组织高1000倍。人类的临床研究已经验证了静脉内治疗的减毒细菌突变体的安全性，建立了多种剂量的耐受性，并表明某些患者发生肿瘤靶向。但是，即使在沙门氏菌被证实已定居肿瘤的患者中，也没有观察到抗肿瘤活性。我们假设可以通过工程凋亡（程序性细胞死亡）来克服人类临床试验中缺乏抗肿瘤功效，从而诱导能够杀死肿瘤细胞的细胞毒性蛋白。该特定目的旨在测试单个蛋白质和蛋白质组合，以发展具有增强抗肿瘤活性的肿瘤靶向沙门氏菌载体。该项目利用合成生物学（DNA的化学合成）来构建编码将杀死癌细胞的蛋白质的基因。这些合成蛋白的组成是基于已知的杀癌和靶向癌症蛋白质成分的组合，这些蛋白质成分在合并后会导致具有杀死癌症的选择性能力的蛋白质。还将进行对细胞凋亡和细胞毒性多肽的新型双功能FUSIO的初步研究提交新的赠款。此处描述的细菌非常安全，适合学生在实验室工作。 PI从微生物学课程中招募了学生，并将他的研究纳入了针对肿瘤的沙门氏菌的研究。还从研究生院录取计划中招募了学生，以及CSUN的MARC和RISE计划。尽管PI仅在CSUN工作了1。5年，但他已经为11名学生提供了基于实验室的研究培训，其中包括3个西班牙裔，2名亚美尼亚人，2名印度人，1名菲律宾人，1名泰国人和1个韩国人。预计该项目将涉及两名研究生在两到三年期间寻求硕士学位，在资助期间总共有多达四名研究生，每年一到两个有指导性的研究本科生；在资金期间，最多八个最多八个，以及在生物学研究课程中注册的每学期一到两个学生，在资助期间总计14至28名学生。