Development of Drugs That Target Prostate Cancer

开发针对前列腺癌的药物

• 批准号: 9153598
• 负责人: William Douglas Figg
• 金额: $ 45.02万
• 依托单位: DIVISION OF BASIC 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/9153598
• 关键词: Adhesions; Adult; Aftercare; Algorithms; Androgen Receptor; Androgens; Antineoplastic Agents; Apoptosis; Area; Attenuated; Biological Assay; Biological Markers; Biological Products; Blood Vessels; CYP17A1 gene; Cancer Cell Growth; Cancer Patient; Cell Line; Cell Proliferation; Cells; Chimeric Proteins; Clinical; Clinical Research; Contrast Media; Cyclin-Dependent Kinases; Data; Detection; Diagnosis; Disease; Disease Progression; Dose; Drug Combinations; EP300 gene; Endothelial Cells; Evaluation; FDA approved; Failure; Flavonoids; Gadolinium; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Human; Hypoxia; Intravenous; KLK3 gene; LNCaP; Lesion; Liver; Liver diseases; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Maximum Tolerated Dose; Measures; Mediating; Metastatic Prostate Cancer; Methods; Microtubule Polymerization; Modeling; Molecular Weight; Monitor; Mus; Necrosis; Neoplasm Metastasis; Organ; Organic Anion Transporters; Oxidation-Reduction; PC3 cell line; Paclitaxel; Patients; Peptides; Phase; Prednisone; Primary carcinoma of the liver cells; Process; Prognostic Marker; Progression-Free Survivals; Property; Prostate carcinoma; Prostatic Neoplasms; Proteins; Publications; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regimen; Relative (related person); Reporting; Resistance; Risk Factors; Safety; Sampling; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Stanolone; Structure; TIE-2 Receptor; TMPRSS2 gene; Taxane Compound; Testosterone; Thalidomide; Therapeutic; Time; Tissues; Toxic effect; Treatment outcome; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Visceral; Weight; Xenograft procedure; abiraterone; analog; angiogenesis; arm; base; cancer cell; cell growth; chemotherapy; chetomin; cytotoxicity; disorder control; docetaxel; drug development; flavopiridol; gadolinium oxide; hypoxia inducible factor 1; imaging agent; imaging modality; improved; inhibitor/antagonist; interest; meetings; men; metastatic process; migration; novel; novel strategies; phase 1 study; phase 2 study; polypeptide; pre-clinical; prevent; prostate cancer cell; prostate cancer cell line; protein expression; randomized trial; resistance mechanism; response; standard of care; targeted treatment; taxane; treatment effect; tumor; tumor growth; tumor progression; uptake

Following the publication of two landmark randomized trials, docetaxel chemotherapy became the standard of care for men with metastatic castrate-resistant prostate cancer (mCRPC). Prior to 2010, docetaxel and prednisone was the only treatment which had demonstrated a survival benefit in patients with mCRPC. Recent advances in the treatment of mCRPC have revolutionized treatment algorithms. Despite their impact on overall survival (OS), sipuleucel-t and alpharadin have unknown impact in symptomatic patients or those with visceral metastasis, respectively. Abiraterone and enzalutamide have favorable toxicity profiles, however they share mechanisms of resistance that likely diminish the benefits of sequential use. Thus, the benefit of these treatment for mCRPC remains limited. Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biological agents. Several new docetaxel-based combinations and novel agents are under evaluation in both the preclinical and clinical setting with promising results. We investigated the selectivity and efficacy of new drug combinations for CRPC. We combined three compounds: paclitaxel (PTX: taxane that inhibits microtubule polymerization); 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole- 1,3(2H)-dione (CPS49; redox-reactive thalidomide analog with anti-angiogenic properties) and flavopiridol (flavo: semisynthetic flavonoid that inhibits cyclin dependent kinases). We found that CPS49 enhanced flavo or PTX cytotoxicity in human PCa cell lines while showed resistance in a non-tumor cell line. Xenografts generated by inoculation of human prostate carcinoma PC3 cells in nu/nu mice showed that CPS49/flavo administration reduced tumor growth both after 2 weeks of co-treatment and after 1 week of pretreatment with a low dose of flavo followed by 2 weeks of co-treatment. PTX and CPS49 combination did not significantly reduce tumor growth in PC3 xenografts. Histological analysis of xenograft PC3 tumor samples from CPS49/flavo combination showed extensive areas of necrosis induced by the treatment. RT-qPCR array containing 23 genes from PC3 cells or PC3 xenografts exposed to CPS49/flavo combination showed that this treatment shut down the expression of several genes involved in adhesion, migration or invasion. In summary, the antitumor activity of CPS49 or flavopiridol was improved by the combination of these compounds and using half dose of that previously reported. Hence, CPS49-flavo combination is a promising new alternative for PCa therapy. We are also interested in understanding the mechanisms of resistance of prostate cancer regimens. Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 alpha (HIF-1a) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1a signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1a inhibition was achieved by siRNA silencing HIF-1a or via chetomin, a disruptor of HIF-1a-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1a target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1a inhibition attenuated AR-regulated and HIF-1a-mediated gene transcription. The combination of enzalutamide and HIF-1a inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1a siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1a inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth. Eovist (Gadoxetate) Enhanced MRI for the Detection of Prostate Cancer: The organic anion transporter polypeptide 1B3 (OATP1B3) is a testosterone transporter expressed de novo in prostate tumors that represents a possible mechanism of prostate tumor growth even in the setting of ADT due to the ability of the cancer cells to scavenge additional testosterone despite low serum testosterone concentrations. There is no current imaging method capable of evaluating the status of the OATP1B3 transporter. Such a method may be important in stratifying risk factors in patients by OATP1B3 status, both with localized and metastatic disease. Eovist is a gadolinium-based contrast agent, which was approved by the FDA in 2008. It is indicated for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease, particularly in the diagnosis of hepatocellular carcinoma. Because Eovist is a low molecular weight imaging agent it rapidly enhances all vascular organs and structures. However, Eovist is not retained by non-OATP1B3 expressing tissue and so at 20 minutes a correlation can be made between OATP1B3 expressing lesions (persistent enhancement) and non-OATP1B3 expressing lesions (washout of enhancement). Thus, we are using Eovist in patients with localized and metastatic prostate cancer in order to determine if this method is feasible to observe differences in uptake times in prostate cancers and whether these differences correlate with OATP1B3 expression in prostate cancer and therefore might serve as a predictive biomarker. Accrual is ongoing. Trebananib (AMG386) is a novel peptide-Fc fusion protein that sequesters angiopoeitin 1 and angiopoeitin 2, thereby preventing their interaction with their common receptor Tie2, and inhibiting tumor endothelial cell proliferation and tumor growth. Dual inhibition of the androgen and angiogenic axis represents a novel strategy of combined targeted therapy for patients with mCRPC. We hypothesize that the addition of trebananib to CYP17 inhibitor abiraterone and prednisone will increase the median progression free survival in chemotherapy-naive mCRPC. This phase 2 study will evaluate the treatment effect as measured by progression free survival in patients treated with trebananib plus abiraterone/prednisone relative to abiraterone/prednisone alone. We are also involved in the biomarker studies in this trial. Analysis of the trial data is ongoing. Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its resistance mechanism. It is an inhibitor of multiple receptor tyrosine kinases including c Met, VEGFR2 and RET. In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities across many solid tumor types. Cabozantinib has yielded one of the highest rates of response with disease control rate, defined as SD or confirmed response, of 68% in CRPC patients. We are involved in a single arm phase I study of fixed dose of docetaxel and prednisone in combination with cabozantinib at three escalating doses too determine the safety profile of cabozantinib in combination with docetaxel and prednisone, and to determine the maximal tolerated dose as recommended phase II dose in combination with docetaxel. Analysis of the trial data is ongoing.

随着两项具有里程碑意义的随机试验的发表，多西他赛化疗成为转移性去势抵抗性前列腺癌（mCRPC）患者的标准治疗方案。在2010年之前，多西紫杉醇和泼尼松是唯一证明mCRPC患者生存获益的治疗方法。mCRPC治疗的最新进展已经彻底改变了治疗算法。尽管sipuleucel-t和alpharadin对总生存期（OS）有影响，但它们分别对有症状的患者或有内脏转移的患者的影响尚不清楚。阿比特龙和恩杂鲁胺具有良好的毒性，但它们具有相同的耐药机制，可能会降低连续使用的益处。因此，这些治疗对mCRPC的益处仍然有限。目前的试验重点是通过将多西紫杉醇与新型生物制剂联合使用来提高疗效。几种基于多西他赛的新组合和新药物正在临床前和临床环境中进行评估，并取得了有希望的结果。我们考察了新组合药物对CRPC的选择性和疗效。我们结合了三种化合物：紫杉醇（PTX：抑制微管聚合的紫杉烷）；2-（2,4-二氟苯基）-4,5,6,7-四氟- h -异吲哚- 1,3(2H)-二酮（CPS49；具有抗血管生成特性的氧化还原反应性沙利度胺类似物）和黄酮吡醇（黄酮：抑制细胞周期蛋白依赖激酶的半合成类黄酮）。我们发现CPS49在人PCa细胞系中增强了黄酮或PTX的细胞毒性，而在非肿瘤细胞系中表现出耐药性。在nu/nu小鼠中接种人前列腺癌PC3细胞产生的异种移植物表明，CPS49/flavo在联合治疗2周后和低剂量黄酮预处理1周后再联合治疗2周后，均能抑制肿瘤生长。PTX和CPS49联合使用对PC3异种移植物的肿瘤生长没有显著的抑制作用。CPS49/flavo组合的异种移植PC3肿瘤样本的组织学分析显示，治疗诱导了广泛的坏死区域。来自PC3细胞或PC3异种移植物暴露于CPS49/flavo组合中的23个基因的RT-qPCR阵列显示，CPS49/flavo组合处理关闭了几个参与粘附、迁移或侵袭的基因的表达。综上所述，CPS49或黄匹吡醇的抗肿瘤活性通过这些化合物的组合和先前报道的一半剂量得到提高。因此，CPS49-flavo组合是一种很有前景的PCa治疗新选择。我们也对了解前列腺癌治疗方案的耐药机制感兴趣。Enzalutamide是一种有效的第二代雄激素受体（AR）拮抗剂，在转移性去势抵抗性前列腺癌（CRPC）中具有活性。虽然恩杂鲁胺最初是有效的，但随着耐药性的出现，疾病不可避免地会进展。肿瘤内缺氧也与CRPC进展和治疗抵抗有关。考虑到AR和缺氧诱导因子-1 α (HIF-1a)都是这些过程的关键调节因子，双重靶向两个信号轴代表了一种有吸引力的治疗方法。在前列腺癌细胞系（LNCaP, 22Rv1）中检测AR和HIF-1a信号通路的串扰，测定雄激素和缺氧对AR依赖和缺氧诱导的基因转录、蛋白表达、细胞增殖和凋亡的影响。HIF-1a抑制是通过siRNA沉默HIF-1a或通过chetomin （HIF-1a-p300相互作用的干扰物）实现的。在前列腺癌细胞中，AR靶点（KLK3、FKBP5、TMPRSS2）的基因表达受到hif信号的抑制；相反，特异的HIF-1a靶表达是由双氢睾酮介导的AR信号传导诱导的。用恩杂鲁胺或HIF-1a抑制剂处理CRPC细胞可减弱ar调控和HIF-1a介导的基因转录。enzalutamide联合HIF-1a抑制比单独治疗更有效。同样，联合用药也降低了血管内皮生长因子蛋白水平。HIF-1a siRNA通过增加enzalutamide诱导的凋亡，协同增强了enzalutamide对LNCaP和enzalutamide耐药22Rv1细胞生长的抑制作用。综上所述，enzalutamide联合HIF-1a抑制可协同抑制ar依赖性和基因特异性hif依赖性表达以及前列腺癌细胞的生长。Eovist （Gadoxetate）增强MRI检测前列腺癌：有机阴离子转运蛋白多肽1B3 （OATP1B3）是一种在前列腺肿瘤中从头表达的睾酮转运蛋白，它代表了前列腺肿瘤生长的可能机制，即使在ADT的情况下，由于癌细胞能够清除额外的睾酮，尽管血清睾酮浓度较低。目前还没有能够评估OATP1B3转运体状态的成像方法。这种方法对于根据OATP1B3状态对局限性和转移性疾病患者的危险因素进行分层可能很重要。Eovist是一种基于钆的造影剂，于2008年获得FDA批准。对于已知或疑似局灶性肝病的成人，特别是肝细胞癌的诊断，在肝脏t1加权磁共振成像（MRI）中静脉注射时，可用于检测和确定病变特征。由于Eovist是一种低分子量显像剂，它可以快速增强所有血管器官和结构。然而，Eovist不被非OATP1B3表达的组织保留，因此在20分钟后，可以在表达OATP1B3的病变（持续增强）和非OATP1B3表达的病变（增强消失）之间建立相关性。因此，我们在局限性和转移性前列腺癌患者中使用Eovist，以确定这种方法是否可行，以观察前列腺癌患者摄取时间的差异，以及这些差异是否与前列腺癌中OATP1B3的表达相关，从而可能作为一种预测性生物标志物。应计项目正在进行中。Trebananib （AMG386）是一种新型肽- fc融合蛋白，可隔离血管生成素1和血管生成素2，从而阻止其与共同受体Tie2的相互作用，抑制肿瘤内皮细胞增殖和肿瘤生长。雄激素和血管生成轴的双重抑制代表了mCRPC患者联合靶向治疗的新策略。我们假设在CYP17抑制剂阿比特龙和强的松的基础上添加曲巴尼将增加化疗初期mCRPC的中位无进展生存期。这项2期研究将评估trebananib联合阿比特龙/强的松治疗患者的无进展生存期，相对于单独使用阿比特龙/强的松。我们也参与了这项试验的生物标志物研究。试验数据的分析正在进行中。Cabozantinib （XL184）是一种血管生成及其耐药机制的抑制剂。它是一种多种受体酪氨酸激酶的抑制剂，包括c Met、VEGFR2和RET。在单药临床研究中，cabozantinib在许多实体肿瘤类型中显示出广泛的抗肿瘤活性。Cabozantinib在CRPC患者中产生了最高的缓解率之一，疾病控制率（定义为SD或确认缓解）为68%。我们参与了一项固定剂量的多西他赛和泼尼松与卡博赞替尼联合三次递增剂量的单臂I期研究，以确定卡博赞替尼与多西他赛和泼尼松联合的安全性，并确定推荐的多西他赛联合II期剂量的最大耐受剂量。试验数据的分析正在进行中。