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

• 批准号: 7939086
• 负责人: ZHENGRONG CUI
• 金额: $ 1.39万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939086
• 关键词: Accounting; Adopted; Adverse effects; Apoptosis; Apoptotic; Biodistribution; Breast; Cancer Model; 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; Medicine; Modality; Modeling; Mus; Oligonucleotides; Outcome; Pancreas; Pancreatic carcinoma; Pathway interactions; Patients; Process; Protein Biosynthesis; Solid; Surface; Testing; Validation; base; cancer cell; cancer therapy; chemotherapy; cytotoxic; eIF-2 Kinase; extracellular; fighting; gemcitabine; human TLR3 protein; improved; in vitro activity; in vivo; intravenous administration; intravenous injection; killings; liver function; mouse model; nanoscale; neoplastic cell; novel strategies; pre-clinical; public health relevance; sound; tumor; tumor growth; uptake

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）：癌症是美国的主要原因之一。化疗仍然是重要的癌症治疗方式。传统上，使用仅激活单一肿瘤杀伤机制的细胞毒性分子。联合化疗现在是一种常见的做法，其中涉及使用几种杀伤机制不同的药物来治疗患者。吉西他滨被批准用于治疗多种癌症：胰腺癌、乳腺癌、肺癌和膀胱癌。尽管吉西他滨对培养的肿瘤细胞非常有效，但吉西他滨在患者中的临床结果相当有限，最近的临床前数据表明，吉西他滨脂质体制剂有助于提高吉西他滨的疗效。最近的一项新进展是使用合成双链 RNA (dsRNA) 作为潜在的化疗药物。某些 dsRNA 分子具有多种直接和间接促凋亡、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 与全身给药的吉西他滨联合给药时，局部注射的合成 dsRNA 的抗肿瘤活性显着增强，这表明使用吉西他滨和 dsRNA 的联合治疗代表了一种有前途的肿瘤治疗方法。然而，对于大多数肿瘤来说，局部瘤周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）缀合的长循环纳米级脂质体 dsRNA 制剂和吉西他滨制剂，以在静脉注射后将其靶向过度表达 EGF 受体的肿瘤细胞，并在小鼠或人类癌症的小鼠模型中验证由此产生的抗肿瘤活性。为了实现我们的总体目标，我们提出以下三个具体目标：(i) 设计用于合成 dsRNA 和吉西他滨的 EGF 包被的长循环脂质体载体，并验证其体外活性，(ii) 评估静脉注射后脂质体载体将 dsRNA 和/或吉西他滨递送到小鼠模型肿瘤中的程度，以及 (iii)评估使用肿瘤靶向脂质体dsRNA和吉西他滨的联合疗法在体内抑制肿瘤生长的程度。该申请的完成将为我们制定策略以改善未来对 dsRNA 和吉西他滨敏感的癌症的临床结果奠定坚实的科学基础。也可以采用类似的策略将 dsRNA 与其他化疗药物结合起来对抗其他肿瘤。公共卫生相关性：许多肿瘤细胞过度表达 EGF 受体。 EGF缀合的长循环脂质体合成dsRNA和脂质体吉西他滨的成功设计以及它们联合使用时的抗肿瘤活性的验证将为未来改善对吉西他滨和dsRNA敏感的肿瘤的临床结果奠定良好的科学基础。类似的策略也可以通过将 dsRNA 与其他化疗药物结合来对抗其他癌症。