IGF-II-Based Approach to Therapy for Pancreatic Cancer

 描述(申请人提供)：胰腺导管腺癌或PDAC是美国癌症死亡的第四大原因，是最具挑战性的癌症之一，难以有效地发现和治疗，五年存活率为6%。PDAC的标准化疗是吉西他滨，它的疗效很低，只会延长几个月的生存时间。迫切需要新的治疗方法，在这项建议中，我们描述了一种关闭胰岛素样生长因子(IGF)轴的新方法。IGF轴与胰腺癌中已发现的12条核心信号通路中的3条相连，并通过刺激有丝分裂和促进生存在许多癌症的病因学中发挥核心作用。IGF-II在PDAC中的作用尚不清楚，但有证据表明，通过与IGF-I受体(IGF1R)或胰岛素受体异构体A(IR-A)结合，IGF-II通过刺激细胞分裂和存活来支持肿瘤的生长。相反，IGF-II与甘露糖6-磷酸/IGF-II受体(M6P/IGF2R)结合导致IGF-II内化和降解，从而下调细胞周围IGF-II水平。M6P/IGF2R还通过其M6P部分与溶酶体酶结合。通过二价M6P配体而不是单价配体(如IGF-II)交叉桥接二聚体M6P/IGF2R两个亚基上的M6P结合位点，可加速受体及其结合货物(包括IGF-II)的内在化3-4倍。这种机制限制了IGF-II与IGF1R/IR-A结合的可能性，IGF1R/IR-A抑制了有丝分裂和生存信号。这项工作的长期目标是开发基于M6P/IGF2R的新疗法，用于IGF-II依赖的癌症。本项目将验证二价M6P配体通过刺激M6P/IGF2R介导的IGF-II处理作为一种潜在的抗PDAC治疗而抑制人胰腺癌细胞生长的假设，具体目的如下：目的1：评估IGF-II和IGF2R在调节胰腺癌细胞增殖和存活中的作用。我们的工作假设是，利用可溶性M6P/IGF2R作为配体陷阱的靶向策略应该能阻断IGF-II驱动的S2-013和Capan-1胰腺癌细胞株的生长。目的：确定基于M6P的多价配体是否能抑制PDAC的异种移植和基因工程小鼠模型的致瘤性。我们的工作假设是，多价M6P配体在体外会抑制肿瘤的致癌特性，并在体内抑制肿瘤的发展。主要的体内肿瘤模型系统将包括将表型标记的胰腺癌细胞原位移植到裸鼠的胰腺包膜中。我们还将在自发性胰腺癌模型中测试它们阻止肿瘤发展的有效性。这些研究将用于验证这一方法，并证明开发基于M6P的多价化合物用于全身给药治疗局部和转移性疾病。

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma or PDAC, the fourth-leading cause of cancer deaths in the U.S, is one of the most challenging cancers to detect and treat effectively, having a five-year survival rate of 6%. Standard chemotherapy for PDAC is gemcitabine, which is minimally efficacious and merely prolongs survival for a few months. Novel therapies are desperately needed, and in this proposal, we describe a new approach to shut down the insulin-like growth factor (IGF) axis. The IGF axis interfaces with 3 of the 12 core signaling pathways identified in pancreatic cancer and plays a central role in the etiology of many cancers by stimulating mitogenesis and promoting survival. The role of IGF-II in PDAC is understudied, but evidence suggests that by binding to the IGF-I receptor (IGF1R) or insulin receptor isoform A (IR-A), IGF-II supports tumor growth by stimulating cell division and survival. In contrast, IGF-II binding to the mannose 6- phosphate/IGF-II receptor (M6P/IGF2R) leads to IGF-II internalization and degradation, which down- regulates pericellular IGF-II levels. The M6P/IGF2R also binds lysosomal enzymes via their M6P moieties. Cross-bridging the M6P binding sites on two subunits of the dimeric M6P/IGF2R by bivalent M6P-based ligands, but not by monovalent ligands such as IGF-II, accelerates internalization of the receptor and its bound cargo, including IGF-II, by 3- to 4-fold. This mechanism limits IGF-II availability for binding to he IGF1R/IR-A, which suppresses mitogenic and survival signaling. The long-term goal of this work is to develop novel M6P/IGF2R-based therapy for IGF-II-dependent cancers. This project will test the hypothesis that bivalent M6P ligands can inhibit human pancreatic cancer cell growth by stimulating M6P/IGF2R- mediated disposal of IGF-II as a potential anti-PDAC therapy, by the following Specific Aims: Aim 1: To assess the roles of IGF-II and the IGF2R in regulating proliferation and survival of pancreatic cancer cells. Our working hypothesis is that targeting strategies utilizing soluble M6P/IGF2R as a ligand trap should disrupt IGF-II-driven growth of S2-013 and Capan-1 pancreatic cancer cell lines. Aim 2: To determine whether multivalent M6P-based ligands can inhibit tumorigenic properties in xenograft and genetically engineered mouse models of PDAC. Our working hypothesis is that multivalent M6P ligands will suppress tumorigenic properties in vitro and inhibit development of tumors in vivo. The main in vivo tumor model system will involve orthotopic transplantation of phenotypically marked pancreatic cancer cells into the pancreatic capsule of the nude mouse. We will also test their efficacy in blocking tumor development in a spontaneous model of pancreatic cancer. These studies will serve to validate the approach and justify development of M6P-based multivalent compounds for systemic administration to treat both local and metastatic disease.