Targeting PHD2 in Pancreatic Cancer

 描述(申请人提供)：胰腺导管腺癌(PDAC)致密的纤维化和异常的肿瘤血管导致肿瘤微环境内低灌注量和间质液体压力(IFP)增加。这严重阻碍了治疗剂的输送，从而限制了药物疗效。因此，减少纤维化或使肿瘤血管正常化的药物可以潜在地改善药物输送并增强药物疗效。事实上，有一些证据表明，NAB-紫杉醇+吉西他滨的组合最近被FDA批准用于治疗PDAC攻击肿瘤间质并增加药物摄取。其他纤维化靶向药物包括透明质酸酶、氯沙坦和CTGF抑制剂也被报道在动物模型中改善药物输送和增强药物疗效。然而，有一类新的基质靶点在PDAC中还没有被广泛研究，那就是Pro羟基酶结构域蛋白(PhDS)。PHD以低氧诱导因子(HIF)为靶点进行降解。PHD2是PHD家族的关键成员，已被证明在肿瘤血管生成和血管正常化中发挥重要作用。在这个方案中，我们建议研究PHD2抑制对肿瘤纤维化和血管形成的影响，并在PDAC的KPC小鼠模型中评价PHD2抑制剂的抗癌活性。我们的假设是，PHD2在PDAC的肿瘤间质和血管调节中起重要作用，抑制PHD2将使PDAC的肿瘤血管正常化，减少纤维化，从而增强药物的输送，提高化疗药物的疗效。本项目的具体目的是：1)研究PHD2抑制对PDAC KPC小鼠模型肿瘤血管和间质结构的影响。我们将研究PHD2抑制剂对血管密度、完整性和间质含量的影响。我们还将确定PHD2抑制剂治疗KPC小鼠后肿瘤血流灌注和药物更新的变化；以及2)研究PHD2抑制剂是否能够增强NAB-紫杉醇和吉西他滨在延长KPC小鼠总生存期方面的疗效。我们的假设是，抑制PHD2导致的肿瘤血流灌注的改善可以转化为对化疗药物如NaB-紫杉醇和吉西他滨的反应改善，从而延长患者的生存时间。我们将进行生存研究，以评估PHD2抑制剂提高活性的能力 NAB-紫杉醇和吉西他滨在KPC小鼠体内的作用。

 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.