Development of Angiogenesis Inhibitors

血管生成抑制剂的开发

• 批准号: 7969756
• 负责人: William Douglas Figg
• 金额: $ 29.74万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969756
• 关键词: AIPC; Adverse effects; Agonist; Androgens; Angiogenesis Inhibition; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Aorta; Binding Proteins; Biological; Biological Factors; Blood Vessels; Cells; Cessation of life; Chemical Structure; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Combined Modality Therapy; Defect; Development; Dose; Double-Blind Method; EP300 gene; Embryo; Endothelial Cells; Enrollment; Evaluation; Family; Gene Expression; Genetic Crossing Over; Gonadotropin Hormone Releasing Hormone; HIF1A gene; Hormone Responsive; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Investigation; Ions; Isoenzymes; Knowledge; Laboratories; Legal patent; Limb structure; Malignant neoplasm of prostate; Metabolic Biotransformation; Modeling; Morphogenesis; Mus; Neutropenia; Oral; PSA level; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Placebos; Prednisone; Property; Prostate Cancer therapy; Prostate-Specific Antigen; Radical Prostatectomy; Randomized; Randomized Controlled Clinical Trials; Rattus; Reporting; Safety; Saphenous Vein; Serum; Solid Neoplasm; Staging; Structure; Supplementation; System; Testing; Testosterone; Thalidomide; Therapeutic; Time; Toxic effect; Toxicology; Transcription Coactivator; Treatment Protocols; Treatment outcome; Tube; Upper arm; Vascular Endothelial Growth Factors; Work; Zinc; analog; angiogenesis; base; bevacizumab; cancer therapy; chemotherapy; chetomin; cytotoxic; design; docetaxel; hormone therapy; human CYP2C19 protein; improved; in vitro Model; in vivo; interest; member; mouse model; outcome forecast; patient population; pre-clinical; prevent; research clinical testing; response; transcription factor; tumor; tumor growth

The angiogenic property of thalidomide reported by D'Amato and colleagues has prompted its clinical evaluation in various solid tumors including prostate cancer. Our laboratory previously showed that one of the products of cytochrome P450 2C19 isozyme biotransformation of thalidomide, 5'-OH-thalidomide, is responsible for the drug's antiangiogenic activity. Based on the chemical structure of this metabolite, we have synthesized 118 analogs of thalidomide and have evaluated them using four in vitro models to assess activity in the inhibition of angiogenesis (rat aorta model, human saphenous vein model, cultured endothelial cells, and tube formationassay). We have identified the most potent of these and have patented them. We are continuing to develop these compounds. These compounds appear have minimal side effects in initial preclinical toxicology studies. Using a randomized Phase II trial design we compared weekly docetaxel (30 mg/m2) with or without 200 mg/d of thalidomide. The objective of this study was to determine whether the combination of thalidomide and docetaxel could produce a sufficiently high clinical response rate to warrant further investigation. A total of 75 patients were enrolled onto this trial, 25 patients in docetaxel alone arm and 50 patients in the combination arm. Both at the midpoint evaluation and at the conclusion of the trial, the proportion of patients with a >50% decline in PSA was higher in the combination arm (25 of 47 patients, 53%) than in the docetaxel alone arm (9 of 24 patients, 37%). The 18 mo survival was 42.9% in the docetaxel alone group and 68.2% in the combined group. The median overall survival in the docetaxel alone group was 14 mo compared with 28 mo for the combination arm (p=0.11) Thalidomide, Docetaxel and Bevacizumab: Dr. Dahut and myself are conducting a Phase II trial of thalidomide, docetaxel, prednisone and bevacizumab in chemo-naive AIPC patients. We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic CRPC. Phase II studies combining docetaxel with bevacizumab have had substantial anti-tumor activity. We hypothesized that the combination docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in both mouse and patients. Sixty patients with progressive metastatic CRPC received i.v. docetaxel and bevacizumab plus oral thalidomide and prednisone. In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. The primary endpoint was a PSA decline of ≥50%. Secondary endpoints included time to progression, overall survival, and safety. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of ≥50% and 88% achieved a PSA decline of ≥30% within the first 3 months of treatment. The median time to progression was 18.3 months and the median overall survival was 28.2 months in this group with a Halabi predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia. The addition of bevacizumab and thalidomide to docetaxel is highly active with manageable toxicities. The estimated median survival is encouraging given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted in order to improve treatment outcomes for patients with metastatic CRPC. Thalidomide in Stage D0 Androgen Dependent Prostate Cancer (ADPC) In 1998, I designed a unique double-blinded randommized Phase III trial to determine if thalidomide could improve the efficacy of LHRH agonists in patients with AIPC, that had a rising PSA level after primary definitive therapy (XRT or radical prostatectomy). A total of 159 patients were enrolled in a double-blind randomized trial to determine if thalidomide can improve the efficacy of a gonadotropin-releasing hormone agonist in hormone responsive patients with an increasing PSA after primary definitive therapy for prostate cancer. Patients were randomized to 6 months of gonadotropin-releasing hormone agonist followed by 200 mg per day oral thalidomide or placebo (oral phase A). At the time of PSA progression gonadotropin-releasing hormone agonist was restarted for 6 additional months. Patients were then crossed over to the opposite drug and were treated until prostate specific antigen progression (oral phase B). During oral phase A the median time to PSA progression was 15 months for the thalidomide group compared to 9.6 months on placebo (p = 0.21). The median time to PSA progression during oral phase B for the thalidomide group was 17.1 vs 6.6 months on placebo (p = 0.0002). No differences in time to serum testosterone normalization between the thalidomide and placebo arms were documented during oral phase A and oral phase B. Thalidomide was tolerable although dose reductions occurred in 47% (58 of 124) of patients. Despite thalidomide having no effect on testosterone normalization, there was a clear effect on prostate specific antigen progression during oral phase B. This is the first study to our knowledge to demonstrate the effects of thalidomide using intermittent hormonal therapy. Epidithiodiketopiperazines block the interaction between hypoxia inducible factor-1alpha (HIF-1alpha) and p300 by a zinc ejection mechanism. The hypoxic response in humans is regulated by the hypoxia inducible transcription factor system; inhibition of HIF activity has potential for the treatment of cancer. Chetomin, a member of the epidithiodiketopiperazine (ETP) family of natural products, inhibits the interaction between HIF-alpha and the transcriptional coactivator p300. Structure-activity studies employing both natural and synthetic ETP derivatives reveal that only the structurally unique ETP core is required and sufficient to block the interaction of HIF-1alpha and p300. In support of both cell-based and animal work showing that the cytotoxic effect of ETPs is reduced by the addition of Zn2+ through an unknown mechanism, our mechanistic studies reveal that ETPs react with p300 causing zinc ion ejection. Cell studies with both natural and synthetic ETPs demonstrated reduction in VEGF reduction and anti-proliferative effects that were abrogated by zinc supplementation. The results have implications for the design of selective ETPs and for the interaction of ETPs with other zinc ion binding protein targets involved in gene expression. Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. In collaboration with Dr. Neil Vargesson, we further investigate the mechanism of action of thalidomide's teratogenic effect. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both th [summary truncated at 7800 characters]

D'Amato及其同事报道的沙利度胺的血管生成特性促使其在包括前列腺癌在内的各种实体肿瘤中的临床评价。我们实验室之前的研究表明，沙利度胺的细胞色素P450 2C19同工酶生物转化的产物之一，5'- oh -沙利度胺，是该药物抗血管生成活性的原因。基于该代谢物的化学结构，我们合成了118种沙利度胺类似物，并利用四种体外模型（大鼠主动脉模型、人隐静脉模型、内皮细胞培养和血管形成实验）对它们进行了评估，以评估其抑制血管生成的活性。我们已经确定了其中最有效的药物，并申请了专利。我们正在继续开发这些化合物。在最初的临床前毒理学研究中，这些化合物的副作用似乎很小。采用随机II期试验设计，我们比较了每周多西他赛（30 mg/m2）与不服用200 mg/d的沙利度胺。本研究的目的是确定沙利度胺和多西他赛联合使用是否能产生足够高的临床反应率，以保证进一步的研究。该试验共有75名患者入组，其中多西他赛单用组25例，联合用药组50例。在中点评估和试验结束时，联合治疗组PSA下降50%的患者比例（47例患者中有25例，53%）高于单独多西紫杉醇治疗组（24例患者中有9例，37%）。多西紫杉醇单独治疗组18个月生存率为42.9%，联合治疗组为68.2%。多西他赛单独治疗组的中位总生存期为14个月，而联合治疗组为28个月（p=0.11）。沙利度胺、多西他赛和贝伐单抗：Dahut博士和我本人正在进行一项沙利度胺、多西他赛、泼尼松和贝伐单抗联合治疗首次化疗AIPC患者的II期试验。我们之前证明，沙利度胺似乎增加了多西他赛在转移性CRPC中的活性。多西紫杉醇联合贝伐单抗的II期研究已经具有显著的抗肿瘤活性。我们假设多西紫杉醇联合这些不同靶点的抗血管生成药物将具有实质性的临床活性。为了探索安全性和有效性，在小鼠和患者中进行了测试。60例进展性转移性CRPC患者静脉注射多西他赛和贝伐单抗联合口服沙利度胺和强的松。在小鼠模型中，多西他赛、贝伐单抗和沙利度胺联合治疗最有效地抑制肿瘤生长。主要终点是PSA下降50%。次要终点包括进展时间、总生存期和安全性。在临床试验中，90%接受联合治疗的患者PSA下降了8805；50%和88%实现PSA下降&amp；#8805；30%在治疗的前3个月内。中位进展时间为18.3个月，中位总生存期为28.2个月，Halabi预测生存期为14个月。虽然毒性可控，但所有患者均出现3/4级中性粒细胞减少症。在多西他赛的基础上加入贝伐单抗和沙利度胺具有高度活性和可控的毒性。估计的中位生存期是令人鼓舞的考虑到一般预后不良的患者群体。这些结果表明，为了改善转移性CRPC患者的治疗结果，有必要将抗血管生成药物与多西他赛联合进行明确的临床试验。1998年，我设计了一项独特的双盲随机III期试验，以确定沙利度胺是否可以提高LHRH激动剂对原发性决定性治疗（XRT或根治性前列腺切除术）后PSA水平升高的AIPC患者的疗效。共有159名患者参加了一项双盲随机试验，以确定沙利度胺是否可以提高促性腺激素释放激素激动剂对原发性前列腺癌终末期治疗后PSA升高的激素应答患者的疗效。患者被随机分配到6个月的促性腺激素释放激素激动剂，随后是每天200毫克口服沙利度胺或安慰剂（口服A期）。在PSA进展时，重新开始使用促性腺激素释放激素激动剂6个月。然后将患者转移到相反的药物治疗，直到前列腺特异性抗原进展（口服B期）。在口服A期，沙利度胺组到PSA进展的中位时间为15个月，而安慰剂组为9.6个月（p = 0.21）。口服B期沙利度胺组到PSA进展的中位时间为17.1个月，而安慰剂组为6.6个月（p = 0.0002）。在口服A期和口服b期期间，沙利度胺组和安慰剂组在血清睾酮正常化的时间上没有差异。沙利度胺是耐受的，尽管有47%（124名患者中的58名）的患者出现了剂量减少。尽管沙利度胺对睾酮正常化没有影响，但在口服b期期间，对前列腺特异性抗原进展有明显影响。据我们所知，这是第一个证明沙利度胺使用间歇性激素治疗效果的研究。附睾二酮哌嗪通过锌喷射机制阻断缺氧诱导因子-1 α (hif -1 α)与p300之间的相互作用。人体缺氧反应受缺氧诱导转录因子系统调控；抑制HIF活性具有治疗癌症的潜力。Chetomin是附睾二酮哌嗪（ETP）家族的天然产物，可抑制hif - α和转录辅激活因子p300之间的相互作用。利用天然和合成ETP衍生物进行的结构-活性研究表明，仅需要结构独特的ETP核心就足以阻断HIF-1alpha和p300的相互作用。为了支持基于细胞和动物的研究，表明ETPs的细胞毒性作用通过未知的机制通过添加Zn2+而降低，我们的机制研究表明ETPs与p300反应导致锌离子喷射。使用天然和合成ETPs进行的细胞研究表明，补锌可以减少VEGF的减少和抗增殖作用。这些结果对选择性etp的设计以及etp与其他参与基因表达的锌离子结合蛋白靶点的相互作用具有指导意义。沙利度胺通过阻止早期肢体形成时血管生成的生长诱导肢体缺损。我们与Neil Vargesson博士合作，进一步研究了沙利度胺致畸作用的作用机制。在这里，我们证明了未成熟血管的损失是沙利度胺诱导畸胎症的主要原因，并提供了其在细胞生物学水平上的作用的解释。沙利度胺的抗血管生成而非抗炎代谢物/类似物诱导小鸡肢体缺损。无论是在体外还是在体内，成熟血管的生长和重塑都会暂时受阻，而新形成的、快速发育的血管生成血管则会丢失。这种血管损失发生在肢体形态发生和基因表达变化的上游，并取决于药物应用的时间，导致胚胎死亡或发育缺陷。这些结果解释了[摘要截短为7800个字符]