Combination therapy using tumor-targeting synthetic dsRNA and gemcitabine

使用肿瘤靶向合成 dsRNA 和吉西他滨的联合治疗

基本信息

批准号：
8043762
负责人：
ZHENGRONG CUI
金额：
$ 27.56万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8043762
关键词：
Accounting Adopted Adverse effects Apoptosis Apoptotic Biodistribution Breast Cause of Death Cell Culture Techniques Cell surface Cessation of life Clinical Clinical Data Combination Drug Therapy Combined Modality Therapy Complex Cytotoxic Chemotherapy Data Development Dose Double-Stranded RNA Drug Delivery Systems Drug Formulations Drug Kinetics Engineering Epidermal Growth Factor Epidermal Growth Factor Receptor Foundations Future Goals Human Immune response In Vitro Injection of therapeutic agent Interferon Type I Intraperitoneal Injections Lead Ligase Liposomes Literature Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Modality Modeling Mus Oligonucleotides Outcome Pancreas Pancreatic carcinoma Particulate Pathway interactions Patients Pharmaceutical Preparations Process Protein Biosynthesis Solid Surface Testing Tumor Tissue Validation base cancer cell cancer therapy chemotherapy cytotoxic ds RNA-Binding Proteins eIF-2 Kinase extracellular fighting gemcitabine human TLR3 protein improved in vitro activity in vivo intravenous administration intravenous injection killings mouse model nanoscale neoplastic cell novel strategies pre-clinical receptor sound tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): Cancer is one of the leading causes of death in the US. Chemotherapy remains an important cancer treatment modality. Traditionally, cytotoxic molecules that activate only a single tumor-killing mechanism are used. Combination chemotherapy is now a common practice, which involves treating patients with several medicines that differ in their killing mechanisms. Gemcitabine is approved for the treatment of various carcinomas: pancreatic, breast, lung, and bladder cancers. Although it is extremely potent in tumor cells in culture, the clinical outcomes of gemcitabine in patients is rather modest, and recent pre-clinical data indicated that a gemcitabine-in-liposome formulation helped improve the efficacy of gemcitabine. A recent new development is the use of synthetic double-stranded RNA (dsRNA) as a potential chemotherapy agent. Certain dsRNA molecules have multiple direct and indirect pro-apoptotic, anti-proliferative, and anti-angiogenic activities. Interestingly, our recent data showed that the anti-tumor activity of a locally injected synthetic dsRNA was significantly enhanced when the dsRNA was dosed in combination with systemically dosed gemcitabine, indicating that a combination therapy using gemcitabine and dsRNA represents a promising tumor therapy approach. However, local peritumoral injection is clinically impractical for the majority of tumors. We propose to develop epidermal growth factor (EGF)-conjugated, long-circulating, nanometer-scale liposomal dsRNA formulation and gemcitabine formulation to target them into EGF receptor-over-expressing tumor cells after intravenous injection and to validate the resultant anti-tumor activity in mouse models of mouse or human cancers. To accomplish our overall goal, we propose the following three specific aims: (i) to engineer EGF-coated, long-circulating liposomal carriers for a synthetic dsRNA and for gemcitabine and to validate their activities in vitro, (ii) to evaluate the extent to which the liposomal carriers will deliver the dsRNA and/or the gemcitabine into model tumors in mice after intravenous injection, and (iii) to evaluate the extent to which a combination therapy using tumor-targeting liposomal dsRNA and gemcitabine will inhibit the tumor growth in vivo. The completion of this application will lay a solid scientific foundation for us to devise strategies to improve the clinical outcome of cancers sensitive to dsRNA and gemcitabine in the future. A similar strategy can also be adopted to combine dsRNA with other chemotherapy agents to fight other tumors. PUBLIC HEALTH RELEVANCE: Many tumor cells over-express the EGF receptor. The successful engineering of EGF-conjugated, long- circulating liposomal synthetic dsRNA and liposomal gemcitabine and the validation of their anti-tumor activities when given in combination will lay a sound scientific foundation for future improvement of the clinical outcomes of tumors sensitive to both gemcitabine and dsRNA. A similar strategy can also be utilized to fight other cancers by combining dsRNA with other chemotherapy agents.

描述（由申请人提供）：癌症是美国的主要死亡原因之一。化学疗法仍然是重要的癌症治疗方式。传统上，仅使用一种仅激活单一肿瘤机制的细胞毒性分子。现在，联合化疗是一种普遍的做法，涉及治疗患者的杀戮机制不同的药物。吉西他滨被批准用于治疗各种癌：胰腺，乳房，肺和膀胱癌。尽管它在培养中的肿瘤细胞中极有效，但吉西他滨在患者中的临床结果相当适中，最近的临床前数据表明，吉西他滨 - 脂质体配方有助于提高吉西他滨的功效。最近的一个新发展是将合成双链RNA（DSRNA）用作潜在的化学疗法剂。某些DSRNA分子具有多个直接和间接的促凋亡，抗增殖和抗血管生成活性。有趣的是，我们最近的数据表明，当DSRNA与全身剂量的吉西他滨结合剂量时，局部注射的合成DSRNA的抗肿瘤活性显着增强，表明使用吉西他滨和DSRNA的组合治疗表明一种有希望的肿瘤治疗方法。但是，对于大多数肿瘤，局部周围注射在临床上是不切实际的。我们建议开发表皮生长因子（EGF）偶联，长循环，纳米尺寸脂质体脂质体DSRNA配方和吉西他滨配方，以将它们靶向静脉内注射后的EGF受体超过表达的肿瘤细胞，并在静脉内注射并验证导致的抗肿瘤抗肿瘤的抗肿瘤活性。 To accomplish our overall goal, we propose the following three specific aims: (i) to engineer EGF-coated, long-circulating liposomal carriers for a synthetic dsRNA and for gemcitabine and to validate their activities in vitro, (ii) to evaluate the extent to which the liposomal carriers will deliver the dsRNA and/or the gemcitabine into model tumors in mice after intravenous injection, and （iii）评估使用涉及肿瘤的脂质体dsRNA和吉西他滨的组合疗法的程度将抑制体内肿瘤的生长。该应用程序的完成将为我们制定策略以改善对DSRNA和吉西他滨敏感的临床结果的稳定科学基础。还可以采用类似的策略将DSRNA与其他化学疗法剂相结合以与其他肿瘤作斗争。公共卫生相关性：许多肿瘤细胞过表达EGF受体。 EGF结合的，长期循环的脂质体合成DSRNA和脂质体吉西他滨的成功工程，当结合使用时，其抗肿瘤活动的验证将为对吉西甲甲苯甲苯；通过将DSRNA与其他化学疗法剂相结合，也可以利用类似的策略来对抗其他癌症。