Targeting PHD2 in Pancreatic Cancer

靶向 PHD2 治疗胰腺癌

• 批准号: 8959593
• 负责人: Haiyong Han
• 金额: $ 20.23万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959593
• 关键词: Animal Model; Beds; Cancer Patient; Cessation of life; Clinical; Collagen; Disease; Drug Delivery Systems; FDA approved; Fibrosis; Genetically Engineered Mouse; Goals; Hyaluronan; Hyaluronidase; Hypoxia Inducible Factor; IL8 gene; Intercellular Fluid; Laminin; Losartan; Malignant Neoplasms; Malignant neoplasm of pancreas; Mus; Oligonucleotides; Outcome; Oxygen; PECAM1 gene; Paclitaxel; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Perfusion; Pharmaceutical Preparations; Play; Procollagen-Proline Dioxygenase; Production; Protein Family; Protein Inhibition; Radiation; Reducing Agents; Reporting; Role; Side; Small Interfering RNA; Solid Neoplasm; Stress; Structure; Tertiary Protein Structure; Therapeutic Agents; Time; Toxic effect; Transforming Growth Factor beta; Translating; Treatment Protocols; Tumor Angiogenesis; Update; Vascular Endothelial Growth Factors; angiogenesis; anticancer activity; chemotherapy; connective tissue growth factor; cytokine; density; drug efficacy; gemcitabine; hypoperfusion; improved; inhibitor/antagonist; member; mouse model; novel; pressure; public health relevance; response; stellate cell; therapeutic target; tumor; tumor growth; tumor microenvironment; uptake

 DESCRIPTION (provided by applicant): The dense fibrosis and abnormal tumor vasculature in pancreatic ductal adenocarcinoma (PDAC) cause hypoperfusion and increased interstitial fluid pressure (IFP) within the tumor microenvironment. This severely impedes the delivery of therapeutic agents and thus limits drug efficacy. Therefore, agents that reduce fibrosis or normalize tumor vasculature can potentially improve drug delivery and enhance drug efficacy. In fact, there is some evidence to show that the nab-paclitaxel + gemcitabine combination recently approved FDA for treatment of PDAC attacks tumor stroma and increases drug uptake. Other fibrosis-targeting agents including hyaluronidase, losartan, and CTGF inhibitors were also reported to improve drug delivery and enhance drug efficacy in animal models. However, one class of novel stromal targets that have not been extensively studied in PDAC is the Prolyl Hydroxylases Domain Proteins (PHDs). PHDs target hypoxia-inducible factors (HIFs) for degradation. PHD2, the key member of the PHD family, has been shown to play an important role in tumor angiogenesis and vessel normalization. In this proposal, we propose to investigate the effect of PHD2 inhibition on tumor fibrosis and vasculature and evaluate the anticancer activity of PHD2 inhibitors in the KPC mouse model for PDAC. Our hypothesis is that PHD2 plays an important role in regulating tumor stroma and vasculature in PDAC and inhibition of PHD2 will normalize tumor vasculature, reduce fibrosis, and subsequently enhance drug delivery and improve the efficacy of chemotherapeutics in PDAC. The specific aims of this project are: 1) to investigate the effects of PHD2 inhibition on tumor vasculature and stromal structure in the KPC mouse model for PDAC. We will examine the effect of PHD2 inhibitors on vessel density and integrity and stromal content. We will also determine the changes in tumor perfusion and drug update upon treatment of PHD2 inhibitors in the KPC mice; and 2) to investigate the ability of PHD2 inhibitors to enhance the efficacy of nab-paclitaxel and gemcitabine in extending the overall survival of KPC mice. Our hypothesis is that improved tumor perfusion resulted from PHD2 inhibition can be translated to improved response to chemotherapeutics such as nab-paclitaxel and gemcitabine and give extended patient survival. We will perform survival studies to evaluate the ability of PHD2 inhibitors to improve the activity of nab-paclitaxel and gemcitabine in the KPC mice.

 描述（由适用提供）：胰腺导管腺癌（PDAC）中的致密纤维化和异常肿瘤脉管系统会导致肿瘤微环境中的间隙液压（IFP）升高和间隙液压（IFP）。这严重阻碍了热药的递送，因此限制了药物效率。因此，减少纤维化或归一化肿瘤脉管系统的药物可以潜在地改善药物递送并提高药物效率。实际上，有一些证据表明，NAB-甲曲奈赛 +吉西他滨的组合最近批准了FDA治疗PDAC攻击肿瘤基质并增加了药物摄取。据报道，其他针对纤维化的靶向剂，包括透明质酸酶，氯沙坦和CTGF抑制剂，可改善药物输送并提高动物模型的药物效率。然而，一类尚未在PDAC中广泛研究的新型基质靶标是羟基羟基酶结构蛋白（PHD）。 PHD靶向缺氧诱导因子（HIF）进行降解。 PHD2是PHD家族的关键成员，已被证明在肿瘤血管生成和血管归一化中起着重要作用。在此提案中，我们建议研究PHD2抑制对肿瘤纤维化和脉管系统的影响，并评估PDAC KPC小鼠模型中PHD2抑制剂的抗癌活​​性。我们的假设是，PHD2在调节PDAC中的肿瘤基质和脉管系统中起着重要作用，并且PHD2的抑制作用将使肿瘤脉管系统归一化，减少纤维化并随后增强药物递送并提高化学治疗药物在PDAC中的有效性。该项目的具体目的是：1）研究PHD2抑制对PDAC的KPC小鼠模型中肿瘤脉管系统和基质结构的影响。我们将检查PHD2抑制剂对血管密度，完整性和基质含量的影响。我们还将在KPC小鼠中治疗PHD2抑制剂后，确定肿瘤灌注和药物更新的变化； 2）研究PHD2抑制剂提高NAB-甲己酰胺和吉西他滨在扩展KPC小鼠整体存活方面的效率的能力。我们的假设是，由PHD2抑制作用导致的改善的肿瘤灌注可以转化为改善对化学治疗剂的反应，例如NAB-甲氟甲酰胺和吉西他滨，并具有扩展的患者生存率。我们将进行生存研究，以评估PHD2抑制剂改善活性的能力 KPC小鼠中的Nab-Paclitaxel和Gemcitabine。