IGF-II-Based Approach to Therapy for Pancreatic Cancer

基于 IGF-II 的胰腺癌治疗方法

• 批准号: 9110216
• 负责人: RICHARD G. MACDONALD
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-14 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110216
• 关键词: Address; Agar; Antibodies; Apoptosis; Area; Back; Binding; Binding Sites; Biogenesis; Biological Assay; Biological Models; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Cell Cycle Arrest; Cell Death; Cell Line; Cell Surface Receptors; Cell Survival; Cell division; Cells; Cessation of life; Clinical Trials; Combination Drug Therapy; Consensus; Databases; Dependence; Development; Disease; Drug Targeting; Drug usage; Endocrine; Enzymes; Etiology; Genetically Engineered Mouse; Goals; Growth; Health; Human; Hybrids; IGF Type 2 Receptor; IGF1R gene; IGF2 gene; IGF2R gene; Immunohistochemistry; In Vitro; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Lead; Ligands; Lysosomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Messenger RNA; Modeling; Nude Mice; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Play; Property; Protein Isoforms; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Somatomedins; Stimulation of Cell Proliferation; Survival Rate; Testing; Therapeutic; Tissue Sample; Tissues; Transplantation; Work; Xenograft procedure; autocrine; base; cancer therapy; capsule; cell growth; cell motility; chemotherapy; gemcitabine; improved; in vivo; inhibitor/antagonist; knock-down; mannose 6 phosphate; migration; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pancreatic cancer cells; pancreatic neoplasm; pancreatic tumorigenesis; paracrine; receptor; receptor internalization; response; small hairpin RNA; small molecule; targeted treatment; tumor; tumor growth; tumorigenic; uptake

 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.

 描述（由申请人提供）：胰腺导管腺癌或PDAC是美国癌症死亡的第四大原因，是最难有效检测和治疗的癌症之一，五年生存率为6%。PDAC的标准化疗是吉西他滨，其疗效最低，仅能延长几个月的生存期。迫切需要新的治疗方法，在这项提案中，我们描述了一种关闭胰岛素样生长因子（IGF）轴的新方法。IGF轴与胰腺癌中确定的12个核心信号传导途径中的3个相互作用，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中的作用研究不足，但有证据表明，通过与IGF-I受体（IGF 1 R）或胰岛素受体亚型A（IR-A）结合，IGF-II通过刺激细胞分裂和存活来支持肿瘤生长。相比之下，IGF-II与甘露糖6-磷酸/IGF-II受体（M6 P/IGF 2 R）的结合导致IGF-II内化和降解，其下调细胞周IGF-II水平。M6 P/IGF 2 R还通过其M6 P部分结合溶酶体酶。通过二价的基于M6 P的配体而不是通过单价配体如IGF-II来交叉桥接二聚体M6 P/IGF 2 R的两个亚基上的M6 P结合位点，将受体及其结合的货物（包括IGF-II）的内化加速3至4倍。这种机制限制了IGF-II与IGF 1 R/IR-A结合的可用性，这抑制了促有丝分裂和存活信号传导。这项工作的长期目标是开发新的基于M6 P/IGF 2 R的治疗IGF-II依赖性癌症的方法。本项目将通过以下具体目的来检验二价M6 P配体可以通过刺激M6 P/IGF 2 R介导的IGF-II处置来抑制人胰腺癌细胞生长作为潜在的抗PDAC疗法的假设：目的1：评估IGF-II和IGF 2 R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M6 P/IGF 2 R作为配体陷阱的靶向策略应该破坏S2-013和Capan-1胰腺癌细胞系的IGF-II驱动的生长。目标二：确定基于多价M6 P的配体是否可以抑制PDAC异种移植和基因工程小鼠模型中的致瘤特性。我们的工作假设是，多价M6 P配体将抑制体外致瘤性和抑制体内肿瘤的发展。主要的体内肿瘤模型系统将涉及将表型标记的胰腺癌细胞原位移植到裸小鼠的胰腺被膜中。我们还将在胰腺癌的自发模型中测试它们在阻断肿瘤发展方面的功效。这些研究将用于验证该方法并证明开发用于全身给药以治疗局部和转移性疾病的基于M6 P的多价化合物的合理性。