A Dual Molecular/Tumor Targeting Therapy for PanCa

描述(由申请人提供)： 在美国，每年大约有3万人被诊断出患有胰腺癌(PANCA)。其中90%以上的人将死于这种疾病，使潘卡成为人类最具破坏性的恶性肿瘤之一。目前不到4%的5年生存率在过去20年中几乎没有变化，尽管治疗方法有所改进，包括引入了吉西他滨(Gemzar)等化疗药物。因此，迫切需要一种改进的治疗方法来治疗80%无法切除和/或转移的胰腺癌。在描述导致PANCA的遗传错误方面取得了进展，从而开辟了新的治疗方法。HER-2原癌基因在60-80%的胰腺癌中过表达。通过反义(AS)方法下调HER-2蛋白可以抑制Panca细胞在体内外的生长。然而，到目前为止，有效的全身性AS寡核苷酸(ODN)递送一直是个问题。我们以抗转铁蛋白受体单链抗体片段(TfRscFv)为靶向实体，研制了一种肿瘤靶向脂质体AS ODN复合体。这种免疫脂质体复合体可以系统地作为HER-2(ODN)递送给胰腺癌，无论其HER-2水平如何。在第一阶段的工作中，我们优化了该复合体，并在原发和原位转移模型中显示了该复合体对Panca肿瘤的系统靶向性，以及由此产生的HER-2下调导致Panca肿瘤细胞在体外和(初步研究)体内对Gemzar的敏感度增加。在这个第二阶段的应用中，我们建议测试优化的TfRscFv-脂质体-HER-2复合体在胰腺癌皮下移植和原位转移模型中的抗肿瘤效果。其他临床试验的先决条件研究，如生物分布和LD10，也将进行，我们将研究使用细胞凋亡的标志物作为一种侵入性较小的方法来评估疗效。此外，我们还将开始探索TfRscFv-脂质体-AS HER-2复合体的组织和结构。我们的最终目标是开发这种系统性的、肿瘤靶向的免疫脂质体作为HER-2复合体，与吉西他滨联合使用，作为一种新颖而有效的治疗方法。这种双重靶向(分子和肿瘤)设计有可能显著扩大抗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 the Phase I work we optimized the complex and have shown systemic targeting of this complex specifically to PanCa tumor, in both primary and an orthotopic metastasis model and that the resultant down modulation of HER-2 leads to an increased sensitization of PanCa tumor cells to Gemzar in vitro and (in preliminary studies) in vivo. In this Phase II application we propose to test the anti-tumor efficacy of the optimized TfRscFv-liposome-AS HER-2 complex in subcutaneous xenograft and orthotopic metastasis models of PanCa. Other studies prerequisite to clinical trials, such as biodistribution and LD10, will also be undertaken and we will examine the use of a marker of apoptosis as a less invasive means to assess efficacy. In addition we will also begin to explore the organization and structure of the TfRscFv-liposome-AS HER-2 complex. 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 targeting (molecular and tumor) design has the potential to significantly expand the therapeutic utility of the anti-HER-2 strategy.