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（由申请人提供）：胰腺导管腺癌（PDAC）中的致密纤维化和异常肿瘤脉管系统导致肿瘤微环境内灌注不足和间质液压力（IFP）增加，这严重阻碍了治疗药物的输送，从而限制了药物疗效。因此，减少纤维化或使肿瘤脉管系统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，最近 FDA 批准白蛋白结合型紫杉醇 + 吉西他滨组合用于治疗 PDAC 攻击肿瘤基质并增加药物摄取，包括透明质酸酶、氯沙坦和 CTGF 抑制剂在内的其他纤维化靶向药物也可改善动物模型中的药物输送并增强药物疗效。脯氨酰羟化酶结构域蛋白 (PHD) 是 PDAC 中尚未广泛研究的一类新型基质靶标。 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。在本提案中，我们建议研究 PHD2 抑制对肿瘤的影响。纤维化和脉管系统，并评估 PHD2 抑制剂在 PDAC 的 KPC 小鼠模型中的抗癌活性。我们的假设是，PHD2 在调节肿瘤基质和脉管系统中发挥重要作用。 PDAC和PHD2的抑制将使肿瘤脉管系统正常化，减少纤维化，从而增强药物输送并提高PDAC中化疗药物的疗效。该项目的具体目的是：1）研究PHD2抑制对肿瘤脉管系统和基质结构的影响。在 PDAC 的 KPC 小鼠模型中，我们将检查 PHD2 抑制剂对血管密度和完整性以及基质含量的影响。我们还将确定肿瘤灌注和药物更新的变化。对 KPC 小鼠进行 PHD2 抑制剂治疗；2) 研究 PHD2 抑制剂增强白蛋白结合型紫杉醇和吉西他滨延长 KPC 小鼠总生存期的功效的能力。转化为改善对白蛋白结合型紫杉醇和吉西他滨等化疗药物的反应，并延长患者的生存期。我们将进行生存研究，以评估 PHD2 抑制剂改善病情的能力。活动 KPC 小鼠体内的白蛋白结合型紫杉醇和吉西他滨。