Development of a plectin-1 targeted payload delivery system for treating pancreat

描述(申请人提供)：胰腺癌在美国癌症相关死亡原因中排名第四，仅在最常见的癌症原因中排名第31位。患者通常患有晚期疾病，众所周知，这种疾病对化疗无效。事实上，5年存活率低于5%。根治性切除辅以化疗是有潜在疗效的，但只有不到15%的患者有资格切除(局部疾病)。尽管进行了几十年的研究，但在PDAC的治疗干预方面仍缺乏有意义的进展。在其他肿瘤学适应症方面，最近在靶向肿瘤治疗有效载荷方面取得了几项临床成功，第一个临床产品很可能于2011年在美国获得批准。因此，该方案的总体目标是开发一种基于分子靶向的纳米颗粒平台，能够直接针对胰腺肿瘤装载和靶向有效的化疗药物。最近，在胰腺癌细胞表面标志物的筛选中，我们发现了一种高度特异的新型细胞表面标志物Plectin-1。Plectin-1通常是一种细胞质蛋白，主要在肌肉和皮肤中表达。但在早期、癌前病变以及迄今检测到的100%的人胰腺肿瘤和转移性病变中，它的表面异常表达(N&gt；100)。Plectin-1在其他一些癌症中表达上调，包括肺癌、卵巢癌和食道癌。一种新的高亲和力和特异性的plectin-1靶向多肽(PTP)已经被鉴定和完全表征。拟议的工作的长期目标是开发一种能够靶向于细胞的灵活的治疗有效载荷输送平台 表达生物标记物plectin-1，如胰腺肿瘤。这些研究的结果将为体外和体内靶向各种胰腺癌细胞系靶向细胞杀伤剂的能力提供可行性数据。将确定一种主导产品，将这项工作推进到第二阶段的工作中，重点放在产品优化、临床前使能毒理学和IND申报上。 与公共卫生相关：这项提案的总体目标是开发一种新的药物输送系统，该系统针对一种新的癌症标签，用于治疗胰腺癌和其他癌症。我们将通过制造能够携带药物的小颗粒来做到这一点，并通过使用识别癌症的标签来针对癌症。开发的靶向药物输送系统最终将用于将多种细胞杀伤剂专门输送到癌细胞，从而有可能延长和改善癌症患者的生命。

DESCRIPTION (provided by applicant): While only the 31st most common cause of cancer, pancreatic cancer is the fourth most common cause of cancer-related death in the US. Patients typically present with advanced disease that is notoriously refractory to chemotherapy. Indeed, the 5 year survival rate is below 5%. Radical resection with adjuvant chemotherapy is potentially curative, but less than 15% of patients qualify for resection (local disease). Despite decades of research, meaningful advancements in the therapeutic intervention of PDAC have been largely absent. In other oncologic indications, there have been several recent clinical successes in targeted tumor delivery of therapeutic payloads, and the first clinical product will likely be approved in the US in 2011. Therefore, the overall goal of this proposal is to develop a molecularly targeted nanoparticle based platform capable of being loaded with and targeting efficacious chemotherapies directly to pancreatic tumors. Recently, in a screen of cell surface markers of pancreatic cancer, we have identified a highly specific and novel cell surface biomarker, Plectin-1. Plectin-1 is normally a cytoplasmic protein predominantly expressed in the muscle and skin. But it is aberrantly surface expressed in in early, precancerous lesions as well as in 100% of human pancreatic tumors and metastatic lesions tested to date (N>100). Plectin-1 is up-regulated in a number of additional cancers including lung, ovarian and esophageal. A novel high-affinity and specific plectin-1 targeting peptide (PTP) that internalizes upon binding has been identified and thoroughly characterized. The proposed work has the long-term objective to develop a flexible therapeutic payload delivery platform capable of targeting to cells expressing the biomarker plectin-1, such as pancreatic tumors. Outcomes from these studies will provide feasibility data on the ability to target cell- killing agents to various pancreatic cncer cell lines in vitro and in vivo. A lead product will be identified for advancing this work to a phae II effort focusing on product optimization, preclinical enabling toxicology and IND filing. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop a new drug delivery system that targets to a novel cancer tag for use in treating pancreatic cancer and other cancers. We will do this by making small particles that are capable of holding drugs and are targeted to the cancer through the use of tags that identify the cancer. The developed targeted drug delivery system will ultimately be used for delivery of numerous cell-killing agents specifically to cancer cells, potentially extending and improving cancer patient's lives.