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）的生存率很低。该项目将 通过开发基于 PaCa 药物治疗的新治疗策略来解决这一障碍 将新鉴定的分子作为维持 PaCa 细胞存活的靶标 新兴新药。我们将在生长的人类胰腺癌细胞中测试这些新兴药物 免疫抑制小鼠证明了针对免疫抑制小鼠量身定制的有效组合策略的可行性 可以分别开发 PaCa 的 Smad4 野生型 (WT) 和突变型 (MT) 亚群。策略 基于细胞生存机制的描述，其中促生存蛋白复合物组成 survivin 和 XIAP 会抑制刽子手 caspase 酶，这种酶通常会杀死正在经历癌症的癌细胞。 癌症微环境的压力。我们实验室发现Smad4突变 导致细胞表面蛋白 RonK 的过量产生，进而激活 修饰存活蛋白/XIAP复合物以增强其稳定性，从而抑制 半胱天冬酶更有效。因此，Smad4 MT 子组的策略之一（大约 PaCa的50%）将是通过新开发的Met家族酪氨酸激酶受体RonK的抑制 来自 Imclone 的单克隆抗体 (IMC-Ron8)。治疗将与同类首创的 YM155 相结合 生存素抑制剂，已被证明会破坏生存素/XIAP 复合物的稳定性，然后 允许半胱天冬酶发挥产生细胞死亡的功能。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 使用一种药物来发挥作用，该药物会导致称为 TGF 受体 II 的肿瘤抑制基因重新表达。这 药物 Belinostat 是一种组蛋白脱乙酰酶抑制剂，可逆转表观遗传信号通路，从而稳定 survivin 和 XIAP。 Smad4 WT 亚组也将与 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小鼠中使用胰腺进行测试 癌症异种移植物，以了解如何最好地向胰腺癌患者施用这些药物。