A Dual Molecular/Targeting Therapy for PanCa

描述（由申请人提供）：美国每年约有30，000人被诊断出患有胰腺癌（PanCa）。超过90%的人会死于这种疾病，使PanCa成为最具破坏性的人类恶性肿瘤之一。目前的5年生存率低于4%，在过去的20年里变化不大，尽管治疗的改善，包括引进化疗药物，如吉西他滨（吉扎）。因此，迫切需要针对80%的不可切除和/或转移性PanCa的改进疗法。已经取得了进展，以描绘遗传错误有助于泛钙，从而开辟了新的治疗方法。HER-2原癌基因在60-80%的PanCa中过表达。通过反义（AS）方法下调HER-2蛋白可以在体外和体内抑制PanCa细胞生长。然而，迄今为止，有效的全身AS寡核苷酸（ODN）递送一直存在问题。我们以抗转铁蛋白受体单链抗体片段（TfRscFv）为靶向实体，构建了一种肿瘤靶向脂质体AS ODN复合物。这种免疫脂质体复合物可以系统地将AS HER-2（ODN）优先递送至PanCa肿瘤，而不管其HER-2水平如何。在初步实验中，HER-2的下调导致PanCa肿瘤细胞对吉西他滨的敏感性增加。在快速通道应用的该I期提案中，我们提出优化用于PanCa细胞的TfRscFv脂质体-ASHER-2复合物。这种优化将不仅导致体外高转染效率，而且在全身递送后导致体内肿瘤特异性靶向。这将使用皮下异种移植物和原位转移小鼠模型来证实。我们还将继续开发具有延长保质期的冻干形式的复合物。我们的最终目标是开发这种全身性的肿瘤靶向免疫脂质体AS HER-2复合物，与吉西他滨联合使用，作为PanCa的一种新型有效的治疗方式。这种双重的分子和肿瘤靶向设计有可能显着扩大抗HER-2策略的治疗效用。

DESCRIPTION (provided by applicant): Approximately 30,000 people in the United States are diagnosed each year with pancreatic Cancer (PanCa). Over 90% of these will die of the disease making PanCa one of the most devastating human malignancies. The current 5-year survival rate of less than 4% has changed little in the last 20 years despite improvements in therapy including the introduction of chemotherapeutic agents such as gemcitabine (gemzar). Thus, there is an urgent need for an improved therapy for the 80% of PanCa that are unresectable and/or metastatic. Progress has been made toward delineating the genetic errors contributing to PanCa thus opening up new approaches to therapy. The HER-2 proto-oncogene is overexpressed in 60-80% of PanCa. Down modulation of HER-2 protein via the antisense (AS) approach can inhibit PanCa cell growth in vitro and in vivo. However, until now efficient systemic AS oligonucleotide (ODN) delivery has been problematic. We have developed a tumor-targeted liposomal AS ODN complex using an anti-transferrin receptor single-chain antibody fragment (TfRscFv) as the targeting entity. This immunoliposome complex can systemically deliver AS HER-2 (ODN) preferentially to PanCa tumors regardless of their HER-2 levels. In preliminary experiments, the resultant down modulation of HER-2 leads to an increased sensitization of PanCa tumor cells to gemzar. In this Phase I proposal of a Fast-Track application we propose to optimize the TfRscFvliposome- AS HER-2 complex for PanCa cells. This optimization will result not only in high transfection efficiency in vitro, but also in tumor specific targeting in vivo after systemic delivery. This will be confirmed using both subcutaneous xenograft and orthotopic metastases mouse models. We will also continue to develop a lyophilized form of the complex with increased shelf life. Our ultimate goal is to develop this systemic, tumor-targeting immunoliposome AS HER-2 complex for use in combination with gemzar as a novel and effective treatment modality for PanCa. This dual, molecular- and tumor-targeting design has the potential to significantly expand the therapeutic utility of the anti-HER-2 strategy.