Novel Strategies for Pancreatic Cancer Treatment

胰腺癌治疗新策略

• 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
• 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

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)存活率很低。这个项目将 通过开发以PACA为基础的药物治疗的新治疗策略来解决这个障碍 在将新鉴定的分子作为维持PACA细胞存活的靶点时，使用 新兴的新药。我们将在人类胰腺癌细胞中测试这些新药物。 免疫抑制小鼠，以证明有效的组合策略是为 可形成PACA的Smad4野生型(WT)和突变型(MT)亚群。策略 是基于对细胞生存机制的描述，在该机制中，促生存蛋白复合体包括 Survivin和XIAP的作用抑制了刽子手caspase酶，这种酶通常会杀死正在经历 癌症微环境的应激状态。我们实验室发现Smad4的突变 导致一种名为RONK的细胞表面蛋白过度生产，进而产生 修饰Survivin/XIAP复合体以增强其稳定性从而使其抑制 半胱氨酸酶的效率更高。因此，Smad4 MT亚组战略的一个分支(大约 50%的PACA)将是一种新开发的对Met家族酪氨酸激酶受体RONK的抑制 免疫单抗(IMC-RON8)。治疗将与YM155相结合，这是同类产品中的第一款 Survivin的抑制剂，已被证明扰乱Survivin/XIAP复合体的稳定，从而 允许半胱氨酸天冬氨酸酶在细胞死亡中的作用。第二个亚群是Smad4 WT，它 代表疾病的另一半，将通过利用Smad4的策略来解决 使用一种药物来重新表达一种名为转化生长因子受体II的肿瘤抑制基因。 组蛋白脱乙酰酶抑制剂Belinostat逆转稳定表观遗传信号通路 Survivin和XIAP都是。Smad4 WT亚群也将与YM155联合治疗，以直接 攻击Survivin的表达。这两种策略都将在免疫抑制的小鼠身上进行测试，使用胰腺 以了解如何最好地将这些药物用于胰腺癌患者。