Neural Progenitor Cells as Cancer Therapy Vectors

神经祖细胞作为癌症治疗载体

基本信息

批准号：
7913870
负责人：
Karen S Aboody
金额：
$ 15.99万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7913870
关键词：
Adenoviruses Anatomy Antineoplastic Agents Carboxylic Ester Hydrolases Cell Line Cells Characteristics Childhood Soft Tissue Sarcoma Clinical Trials Complement component C1s Complementary DNA Cyclosporins Data Disease Disseminated Malignant Neoplasm Dose Enzymes Fishes Genome Glioblastoma Goals Hematopoiesis Human In Vitro Injection of therapeutic agent Large Intestine Carcinoma Length Localized Disease Location Long-Term Effects Malignant Epithelial Cell Malignant neoplasm of lung Malignant neoplasm of prostate Metastatic to Micrometastasis Modeling Molecular Mus Neoplasm Metastasis Neuroblastoma Normal tissue morphology Organ Oryctolagus cuniculus Patients Plasma Prodrugs Property Publishing Research Personnel Resectable Residual Tumors SCID Mice SN-38 Schedule Site Solid Neoplasm Tail Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Transgenes Treatment Efficacy Tropism Tumor Burden Veins Viral base cancer therapy carboxylesterase cytotoxicity effective therapy esterase in vivo intravenous administration malignant breast neoplasm mouse model neoplastic cell nerve stem cell outcome forecast pre-clinical programs research study therapeutic transgene transgene expression tumor v-myc Gene vector

项目摘要

DESCRIPTION (provided by applicant): Almost without exception, patients with localized tumors have better prognoses than patients with metastatic disease. The long-range goal of our studies is to develop safe, effective, systemic treatments for metastatic solid tumors. The basis of the approach described in this application is the use of neural progenitor cells (NPCs) to deliver cDNAs encoding therapeutic transgenes selectively to metastatic tumor loci. We propose to determine whether the tumor-tropic property of intravenously injected NPCs can be exploited to deliver the cDNA encoding a CPT-11-activating enzyme selectively to metastatic tumor sites. We will evaluate whether subsequent administration of CPT-11 to mice with metastatic neuroblastoma (NB) will eradicate micrometastatic disease. Preliminary and published data show that NPCs given by tail vein injection migrate to tumor loci regardless of the anatomic location of the tumors in mouse models. Preliminary data also show that NPCs transduced with replication-defective adenovirus encoding the CPT-11-activating enzyme rabbit carboxylesterase (rCE) express up to 1000-fold higher levels of CE activity than do human normal or tumor cells. The data support the hypothesis that intravenous administration of NPCs encoding rCE and CPT-11 may produce levels of SN-38 at tumor loci sufficient to eradicate residual disease, but minimize toxicity. Efficacy and toxicity studies will be done using esterase-deficient Es1e/SCID mice bearing disseminated NB. Preliminary Data show that NPCs migrate to metastatic NB tumors, and clinical trials indicate that CPT-11 has potential for the treatment of NB. This study is intended to show proof of principle specifically regarding the efficacy of NPC-directed enzyme prodrug therapy (NDEPT) with rCE and CPT-11 for NB. However, preclinical data document that NPCs also migrate to loci of several types of solid tumors such as glioblastoma and breast cancer. Therefore, the data generated may also provide proof of principle for the more general hypothesis that NPCs can be used as effective tumor-specific delivery vectors for therapeutic cDNAs. The described approach might then be adapted to the treatment of other solid tumors by careful choice of appropriate therapeutic transgenes.

描述（由申请人提供）：几乎无一例外，患有局部肿瘤的患者比患有转移性疾病的患者具有更好的预后。我们研究的长期目标是开发安全、有效、系统的转移性实体瘤治疗方法。本申请中描述的方法的基础是使用神经祖细胞(NPC)将编码治疗性转基因的cDNA选择性地递送至转移性肿瘤位点。我们建议确定是否可以利用静脉注射 NPC 的亲肿瘤特性将编码 CPT-11 激活酶的 cDNA 选择性地递送至转移性肿瘤部位。我们将评估随后对患有转移性神经母细胞瘤 (NB) 的小鼠施用 CPT-11 是否会根除微转移性疾病。初步和已发表的数据表明，无论小鼠模型中肿瘤的解剖位置如何，通过尾静脉注射给予的 NPC 都会迁移到肿瘤位点。初步数据还表明，用编码 CPT-11 激活酶兔羧酸酯酶 (rCE) 的复制缺陷型腺病毒转导的 NPC 表达的 CE 活性水平比人类正常细胞或肿瘤细胞高 1000 倍。这些数据支持这样的假设：静脉内注射编码 rCE 和 CPT-11 的 NPC 可能会在肿瘤位点产生足以根除残余疾病的 SN-38 水平，同时将毒性降至最低。将使用带有播散性 NB 的酯酶缺陷 Es1e/SCID 小鼠进行功效和毒性研究。初步数据显示NPC迁移至转移性NB肿瘤，临床试验表明CPT-11具有治疗NB的潜力。本研究旨在展示有关 NPC 导向的酶前药疗法 (NDEPT)（使用 rCE 和 CPT-11）治疗 NB 的功效的原理证明。然而，临床前数据表明，NPC 也会迁移到胶质母细胞瘤和乳腺癌等几种实体瘤的位点。因此，生成的数据还可以为更普遍的假设提供原理证明，即 NPC 可用作治疗性 cDNA 的有效肿瘤特异性递送载体。然后，通过仔细选择适当的治疗性转基因，所描述的方法可能适用于其他实体瘤的治疗。