Novel Strategies for Pancreatic Cancer Treatment

胰腺癌治疗新策略

基本信息

批准号：
8738890
负责人：
MICHAEL G BRATTAIN
金额：
$ 36.41万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738890
关键词：
Address Antibodies Apoptosis Apoptotic Area Autopsy BIRC4 gene Cancer Model Cancer Patient Caspase Cell Death Cell Surface Proteins Cell Survival Cells Clinical Clinical Trials Combined Modality Therapy Complex Coupled Cyclic AMP-Dependent Protein Kinases Development Diagnosis Disease Disease Progression Drug Combinations Environment Enzyme Activation Enzymes Epigenetic Process Event Family Family member Future Genetic Genetic Transcription Goals Histone Deacetylase Histone Deacetylase Inhibitor Human In Vitro Investigation Laboratories Learning MADH4 gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Molecular Monoclonal Antibodies Mus Mutation Neoplasm Metastasis Pathway interactions Patients Pattern Pharmaceutical Preparations Pre-Clinical Model Proteins Receptor Protein-Tyrosine Kinases Relative (related person)Reporting Sampling Signal Pathway Signal Transduction Solid Neoplasm Staging Stress Subgroup Survival Rate Testing Therapeutic Therapeutic Index Time Tissues Treatment Effectiveness Tumor Suppressor Genes Tumor Suppressor Proteins Validation Xenograft procedure advanced disease arm base cancer cell cancer therapy cell type effective therapy immunosuppressed improved in vivo inhibitor/antagonist killings meetings multicatalytic endopeptidase complex mutant novel novel strategies novel therapeutics pancreatic cancer cells programs protein complex receptor receptor expression research study response subcutaneous survivin

项目摘要

Pancreatic cancer (PaCa) carries a poor survival due to lack of effective drug treatment. This project will address this barrier through the development of new therapeutic strategies for drug treatment of PaCa based upon the targeting of newly identified molecules as targets for maintaining the survival of PaCa cells using emerging novel drugs. We will test these emerging drugs in human pancreatic cancer cells grown in immunosuppressed mice to demonstrate the feasibility that effective combination strategies tailored for the Smad4 wild type (WT) and mutant (MT) subgroups of PaCa, respectively, can be developed. The strategies are based upon description of a cell survival mechanism in which a pro-survival protein complex consisting of survivin and XIAP inhibits the executioner caspase enzymes that would normally kill cancer cells undergoing the stress of the cancer micro-environment. Our laboratory has found that the mutation of Smad4 leads to the overproduction of a cell surface protein called RonK that in turn generates the activation of enzymes that modify the survivin/XIAP complex to enhance its stability and thereby make the inhibition of caspases more efficient. Consequently, one arm of the strategy for the Smad4 MT subgroup (approximately 50% of PaCa) will be the inhibition of the Met family tyrosine kinase receptor RonK by a newly developed monoclonal antibody from Imclone (IMC-Ron8). Treatment will be coupled with YM155, a first-in-its-class inhibitor of survivin, which has been shown to disrupt the stabilization of survivin/XIAP complexes that then permits the function of caspases in generating cell death. The second subgroup is Smad4 WT, which represents the other half of the disease, will be addressed by a strategy that takes advantage of Smad4 function using a drug that cause re-expression of a tumor suppressor gene called TGF¿ receptor II. The drug, Belinostat, a histone deacetylase inhibitor reverses the epigenetic signaling pathway that stabilizes both survivin and XIAP. The Smad4 WT subgroup will also be treated in combination with YM155 to directly attack the expression of survivin. Both strategies will be tested in immunosuppressed mice using pancreatic cancer xenografts in order to learn how best to administrate these drugs to pancreatic cancer patients.

由于缺乏有效的药物治疗，胰腺癌（PACA）的生存率差。这个项目将通过制定基于PACA的药物治疗的新治疗策略来解决这一障碍靶向新鉴定的分子作为维持PACA细胞存活的靶标。新兴的新药。我们将在人类胰腺癌细胞中测试这些新兴药物免疫抑制小鼠，以证明可行性是为了量身定制的有效组合策略可以开发PACA的SMAD4野生型（WT）和突变体（MT）亚组。策略基于对细胞存活机制的描述，其中促生存蛋白络合物组成 Survivin和XIAP的抑制execution子caspase酶通常会杀死正在接受的癌细胞癌症微环境的应力。我们的实验室发现Smad4的突变导致称为ronk的细胞表面蛋白的生产过多，进而产生激活修饰rovivin/xiap复合物以增强其稳定性并从而抑制的酶 caspase效率更高。因此，SMAD4 MT子组的策略的一个部门（大约 PACA的50％）将通过新发展 IMCLONE（IMC-RON8）的单克隆抗体。治疗将与YM155耦合，这是第一类 Survivin的抑制剂，该抑制剂已被证明破坏了Survivin/XIAP复合物的稳定允许胱天蛋白酶的功能产生细胞死亡。第二个子组是smad4 wt，代表疾病的另一半，将通过利用SMAD4的策略来解决功能使用导致称为TGF抑制基因II的肿瘤抑制基因的药物。这药物，Belinostat，一种组蛋白脱乙酰基酶抑制剂可逆转稳定的表观遗传信号通路 Survivin和Xiap均均可。 SMAD4 WT亚组也将与YM155联合处理攻击Survivin的表达。两种策略将在免疫抑制的小鼠中使用胰腺测试癌症的Xenographictic是为了了解如何最好地管理这些药物给胰腺癌患者。