Interactions of the angiopoietin and PD-ECGF pathways in tumor angiogenesis

血管生成素和 PD-ECGF 通路在肿瘤血管生成中的相互作用

• 批准号: 8676737
• 负责人: EDWARD L SCHWARTZ
• 金额: $ 33.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676737
• 关键词: Adherens Junction; Adhesives; Angiogenesis Inhibitors; Angiogenic Factor; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Biological; Blood Vessels; Carcinoma; Cells; Clinical; Clinical Trials; Complement; Desmoplastic; Drug Kinetics; Drug Targeting; Drug effect disorder; Endocrine; Endothelial Cells; Event; Exocrine pancreas; Future; Genes; Genetic; Grant; Growth; Image; Incidence; Intercellular Junctions; Islet Cell Tumor; Knock-out; Lead; Link; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Morphology; Mus; Neoplasm Metastasis; Neuroendocrine Cell; Neurosecretory Systems; Normal Cell; Operative Surgical Procedures; PTK2 gene; Pancreas; Pathway interactions; Patients; Pericytes; Pharmaceutical Preparations; Pharmacodynamics; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Phosphorylation; Plasma; Population; Proteins; Randomized; Refractory; Role; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Stromal Cells; Surgeon; Surrogate Markers; Survival Rate; System; TEK gene; Thymidine; Thymidine Phosphorylase; Tight Junctions; Toxic effect; Tumor Angiogenesis; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascularization; base; cadherin 5; capsule; chemotherapy; cytokine; human disease; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; macrophage; monocyte; mouse model; neoplastic cell; novel; novel strategies; overexpression; pancreatic cancer cells; pancreatic neoplasm; pre-clinical; research study; response; small molecule; tumor; vector

DESCRIPTION (provided by applicant): Drugs that target tumor angiogenesis can increase response rates and survival in patients with advanced malignancies, although the percentage of patients responding is generally low. Recent clinical trials suggest that most advanced pancreatic exocrine carcinomas are refractory to angiogenesis inhibitors, and this may be due to the hypovascularity and other biological features of these tumors. In contrast to the more common exocrine pancreatic cancers, malignancies originating from neuroendocrine cells in the pancreas, called pancreatic neuroendocrine tumors (PNET), lack a desmoplastic fibroinflammatory capsule and are highly vascularized. While metastatic PNET are not cured by surgery or chemotherapy, objective responses of PNET to anti-angiogenic agents have been seen in mouse models and in randomized phase III clinical trials. Since pancreatic cancers often express multiple angiogenic factors, an objective of this proposal is to determine if combinations of inhibitors targeting different angiogenic factors are effective in mouse models of PNET. The inhibitors to be studied include a novel, highly specific, orally available small molecule inhibito of the angiogenic factor thymidine phosphorylase (TP) which we have synthesized, and two highly specific peptibodies which neutralize the angiogenic factors angiopoietin-1 (Ang-1) and Ang-2. The second objective of this proposal is to determine the role of TP, and the mechanisms of action of our TP inhibitor, in vivo. Included in this objective are studies that are based on the unexpected discovery of a direct link between the angiopoietin/TIE system and TP, observed in a subset of tumor-associated macrophages (TAMs) called TEMs (TIE2-expressing monocytes/ macrophages). These studies could form the basis for new therapies to treat pancreatic cancer, and could be readily extrapolated to other solid tumor types. The specific aims are: 1) to conduct pharmacokinetic and pharmacodynamic (PK/PD) studies of AEAC in normal and tumor-bearing mice, and to determine if it produces host toxicity; 2) to determine the anti- angiogenic and antitumor activities of AEAC when used in combination inhibitors of angiopoietin and/or VEGF pathways; 3) to determine the mechanisms of action of TP and AEAC in vivo, including effects on downstream signaling events in tumor endothelial cells and effects on vasculature morphology and normalization, and to determine if TP expression is regulated in vivo by Ang-2; and 4) to use genetic approaches to assess the effect of TP on tumor vascularization and progression in vivo, including the manipulation of the pancreatic cancer cells and tumor stromal cells, particularly TAMs and TEMs. Among the in vivo models to be used is a genetic mouse model which has a conditional knockout of the Men1 gene in the endocrine pancreatic cells (Pdx1- Cre;Men1 mice). These mice develop pancreatic endocrine tumors that closely mimic the human disease both in genetic origin and phenotype, including increased expression of angiogenic factors, and respond therapeutically to treatment with angiogenesis inhibitors.

描述（由申请人提供）：针对肿瘤血管生成的药物可以提高晚期恶性肿瘤患者的反应率和生存率，尽管患者反应的百分比通常较低。最近的临床试验表明，大多数晚期胰腺外分泌癌对血管生成抑制剂具有耐药性，这可能是由于这些肿瘤的血管不足和其他生物学特征所致。与更常见的外分泌胰腺癌相反，源自胰腺神经内分泌细胞的恶性肿瘤，称为胰腺神经内分泌肿瘤（PNET），缺乏促纤维增生性纤维炎性包膜并且高度血管化。虽然转移性 PNET 无法通过手术或化疗治愈，但在小鼠模型和随机 III 期临床试验中已经观察到 PNET 对抗血管生成药物的客观反应。由于胰腺癌通常表达多种血管生成因子，因此该提案的一个目标是确定针对不同血管生成因子的抑制剂组合在 PNET 小鼠模型中是否有效。待研究的抑制剂包括我们合成的新型、高度特异性、口服小分子血管生成因子胸苷磷酸化酶（TP）抑制剂，以及中和血管生成因子血管生成素-1（Ang-1）和Ang-2的两种高度特异性肽体。该提案的第二个目标是确定 TP 的作用以及我们的 TP 抑制剂的体内作用机制。该目标中包括基于血管生成素/TIE系统与TP之间直接联系的意外发现的研究，在称为TEM（表达TIE2的单核细胞/巨噬细胞）的肿瘤相关巨噬细胞（TAM）子集中观察到。这些研究可以为治疗胰腺癌的新疗法奠定基础，并且可以很容易地推广到其他实体瘤类型。 具体目的是：1）在正常小鼠和荷瘤小鼠中进行AEAC的药代动力学和药效学（PK/PD）研究，并确定其是否产生宿主毒性； 2)确定AEAC与血管生成素和/或VEGF途径的组合抑制剂一起使用时的抗血管生成和抗肿瘤活性； 3)确定TP和AEAC在体内的作用机制，包括对肿瘤内皮细胞下游信号传导事件的影响以及对脉管系统形态和正常化的影响，并确定TP表达在体内是否受Ang-2调节； 4) 使用遗传学方法评估 TP 对体内肿瘤血管化和进展的影响，包括操纵胰腺癌细胞和肿瘤基质细胞，特别是 TAM 和 TEM。所使用的体内模型是遗传小鼠模型，该模型在内分泌胰腺细胞中条件性敲除Men1基因（Pdx1-Cre；Men1小鼠）。这些小鼠产生的胰腺内分泌肿瘤在遗传起源和表型上都与人类疾病非常相似，包括血管生成因子表达增加，并对血管生成抑制剂的治疗有反应。