Maximization of anti-angiogenesis by thrombospondin-1

血小板反应蛋白-1 最大限度地抑制血管生成

• 批准号: 7471438
• 负责人: OLGA Valery VOLPERT
• 金额: $ 26.94万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471438
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Angiogenesis Inhibitors; Angiogenic Peptides; Angiogenic Proteins; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Biochemical; Biological; Biological Assay; CD36 gene; CD95 Antigens; Cell Death; Cells; Cessation of life; Characteristics; Cisplatin; Class; Collaborations; Combined Modality Therapy; Cornea; Cyclophosphamide; Data; Disease; Dose; Doxorubicin; Endothelial Cells; Endothelium; Fibroblast Growth Factor 2; Flow Cytometry; Growth; Human; Immunohistochemistry; In Vitro; Inhibition of Apoptosis; Invasive; LNCaP; Ligands; Link; Malignant - descriptor; Measures; Mediator of activation protein; Metabolic; Methods; Modeling; Mus; Mutagens; Nuclear Receptors; Peptides; Pericytes; Pharmacologic Substance; Phenotype; Pioglitazone; Predisposition; Prostate carcinoma; Rate; Receptor Signaling; Role; SR-BI receptor; Signal Transduction; Stimulus; Surface; TNFRSF6 gene; Testing; Thrombospondin 1; Toxic effect; Toxicity due to chemotherapy; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Volume; Vascular Endothelium; Vascularization; angiogenesis; antiangiogenesis therapy; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; cytotoxic; decoy receptor 3; docetaxel; improved; in vivo; inhibitor/antagonist; matrigel; migration; neutralizing antibody; novel strategies; receptor; response; rosiglitazone; troglitazone; tumor; tumor growth

DESCRIPTION (provided by applicant): Anti-angiogenic thrombospondin-1 (TSP1) binds CD36 receptor to trigger apoptosis in vascular endothelium. This causes a secondary signal via CD95/Fas, a death receptor expressed independent of TSP1 by remodeling endothelium. TSP1 increases CD95 cognate ligand, FasL, which binds inducer-generated Fas causing apoptosis. DI-TSP, a short TSP-derived inhibitory peptide generates identical signal. Thus the sensitivity to inhibitory TSP1/DI-TSP is limited by the availability of its primary (CD36), or secondary (CD95) signaling receptors. We aim to improve susceptibility to DI-TSP by modulating the levels of these rate-limiting signaling mediators. We will modulate CD36 using synthetic ligands of the PPARy nuclear receptor. CD95 we will alter with low-dose continuous (metronomic) chemotherapy. We propose to study: 1. The effects of the low-dose genotoxic agents on DI-TSP specific activity. We will measure Fas and FasL in human microvascular cells (HMVECs) treated with DI-TSP and/or low dose chemotherapy and compare the effects of DI-TSP and/or chemotherapy on the endothelial (EC) and cancer cell phenotype, Fas and FasL presentation, apoptosis and migration. Antibodies, Fas decoy receptor and metabolic inhibitors will be used to link CD95 increase with TSP1 augmented activity. 2. The effects of metronomic chemotherapy DI-TSP angiosuppression in vivo. Mice bearing bFGF-containing Matrigel plugs will be treated with DI-TSP and/or metronomic chemotherapy. The effect on vascularity, Fas and FasL expression, the extent of endothelia l cell apoptosis and pericyte recruitment will be measured. Antibodies, Fas decoy receptor and metabolic inhibitors will be used to link CD95 increase with TSP1 augmented activity. 3. The effects of thiazolinediones (TZDs, synthetic PPARy ligands) on CD36 expression and TSP1 anti-angiogenic activity. EC apoptosis, inhibition of migration, proliferation will be used to determine non-cytotoxic doses of troglitazone, rosiglitazone and pioglitazone, to achieve maximal CD36 increase. These doses will be tested in vivo in matrigel plug assay. CD36 neutralizing antibodies will be used to determine its contribution in vitro and in vivo. 4. The effect of TSP-based combination therapies on tumor growth and angiogenesis. TZDs and metronomic chemotherapy will be used alone and in combination with DI-TSP to block or delay the growth of invasive PC-3 or of less aggressive LNCaP prostate carcinoma. Tumor volume, angiogenesis, EC and non-EC apoptosis will be measured. Angiogenesis inhibitors comprise a new class of anti-cancer drugs. We showed that combining anti-angiogenics with chemotherapy offers possibility to significantly cut the dose and therefore the toxicity of chemotherapy while achieving substantial improvement in the efficacy of an anti-angiogenic. Such combined therapies present a promising new approach to the treatment of cancer and other angiogenesis dependent diseases.

描述（由申请人提供）：抗血管生成血栓反应蛋白-1 （TSP1）结合CD36受体触发血管内皮细胞凋亡。这通过CD95/Fas（一种独立于TSP1表达的死亡受体，通过重塑内皮细胞）引起二次信号。TSP1增加CD95同源配体FasL， FasL结合诱导剂产生的Fas导致细胞凋亡。DI-TSP是一种短的tsp衍生的抑制肽，产生相同的信号。因此，对抑制TSP1/DI-TSP的敏感性受到其主要（CD36）或次要（CD95）信号受体的可用性的限制。我们的目标是通过调节这些限速信号介质的水平来提高对DI-TSP的敏感性。我们将使用合成的pparty核受体配体来调节CD36。CD95我们将改变低剂量连续（节拍）化疗。我们建议研究：1。低剂量基因毒性制剂对DI-TSP特异性活性的影响。我们将测量经DI-TSP和/或低剂量化疗处理的人微血管细胞（HMVECs）中的Fas和FasL，并比较DI-TSP和/或化疗对内皮细胞（EC）和癌细胞表型、Fas和FasL呈现、凋亡和迁移的影响。抗体、Fas诱饵受体和代谢抑制剂将用于将CD95增加与TSP1增强活性联系起来。2. 节律化疗DI-TSP对体内血管抑制的影响。植入含bfgf的Matrigel塞的小鼠将接受DI-TSP和/或节律化疗。测定其对血管、Fas和FasL表达、内皮细胞凋亡程度和周细胞募集的影响。抗体、Fas诱饵受体和代谢抑制剂将用于将CD95增加与TSP1增强活性联系起来。3. 噻唑啉二酮（TZDs，合成pparty配体）对CD36表达和TSP1抗血管生成活性的影响。通过对EC凋亡、迁移抑制、增殖的影响来确定罗格列酮、罗格列酮和吡格列酮的非细胞毒性剂量，以达到CD36的最大增加。这些剂量将在基质塞实验中进行体内测试。CD36中和抗体将用于确定其在体外和体内的作用。4. 基于tsp的联合治疗对肿瘤生长和血管生成的影响。TZDs和节律化疗将单独使用或与DI-TSP联合使用，以阻断或延缓侵袭性PC-3或侵袭性较低的LNCaP前列腺癌的生长。测量肿瘤体积、血管生成、内皮细胞和非内皮细胞凋亡。血管生成抑制剂是一类新的抗癌药物。我们发现，将抗血管生成药物与化疗相结合，可以显著减少剂量，从而降低化疗的毒性，同时显著提高抗血管生成药物的疗效。这种联合疗法为治疗癌症和其他血管生成依赖性疾病提供了一种有希望的新方法。