Combination therapy using tumor-targeting synthetic dsRNA and gemcitabine

描述（由申请人提供）：癌症是美国死亡的主要原因之一。化疗仍然是一种重要的癌症治疗方式。传统上，只使用激活单一肿瘤杀伤机制的细胞毒分子。联合化疗现在是一种常见的做法，它包括用几种杀伤机制不同的药物治疗患者。吉西他滨被批准用于治疗各种癌症：胰腺癌、乳腺癌、肺癌和膀胱癌。尽管吉西他滨在培养的肿瘤细胞中非常有效，但其在患者中的临床结果相当温和，最近的临床前数据表明，脂质体中的吉西他滨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）作为一种潜在的化疗药物。某些dsRNA分子具有多种直接和间接的促凋亡、抗增殖和抗血管生成活性。有趣的是，我们最近的数据显示，局部注射的合成dsRNA与全身给药的吉西他滨联合给药时，其抗肿瘤活性显著增强，这表明吉西他滨和dsRNA联合治疗是一种很有前景的肿瘤治疗方法。然而，对于大多数肿瘤，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）偶联的、长循环的、纳米级脂质体dsRNA制剂和吉西他滨制剂，在静脉注射后靶向EGF受体过表达的肿瘤细胞，并在小鼠或人类癌症模型中验证由此产生的抗肿瘤活性。为实现总体目标，我们提出以下三个具体目标：(i)为合成dsRNA和吉西他滨设计egf包被的长循环脂质体载体，并在体外验证其活性；（ii）评估脂质体载体在静脉注射后将dsRNA和/或吉西他滨输送到小鼠肿瘤模型中的程度；（iii）评估肿瘤靶向脂质体dsRNA和吉西他滨联合治疗在体内抑制肿瘤生长的程度。本次申请的完成将为我们未来制定改善对dsRNA和吉西他滨敏感的癌症临床结局的策略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：许多肿瘤细胞过表达EGF受体。egf结合的长循环脂质体合成dsRNA和脂质体吉西他滨的工程成功，以及两者联合给药时抗肿瘤活性的验证，将为今后改善吉西他滨和dsRNA均敏感的肿瘤临床疗效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。

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.