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.

在两项具有里程碑意义的随机试验发表后，多西紫杉醇化疗成为男性转移性去势抵抗性前列腺癌 (mCRPC) 的治疗标准。 2010 年之前，多西紫杉醇和泼尼松是唯一已证明对 mCRPC 患者有生存益处的治疗方法。 mCRPC 治疗的最新进展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有未知的影响。阿比特龙和恩杂鲁胺具有良好的毒性特征，但它们具有共同的耐药机制，可能会削弱序贯使用的益处。因此，这些治疗对 mCRPC 的益处仍然有限。目前试验的重点是通过将多西紫杉醇与新型生物制剂相结合来提高其疗效。几种新的基于多西紫杉醇的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。我们研究了 CRPC 新药组合的选择性和功效。我们组合了三种化合物：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-1H-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flavopiridol（flavo：抑制细胞周期蛋白依赖性激酶的半合成类黄酮）。我们发现 CPS49 增强人前列腺细胞系中的黄酮或 PTX 细胞毒性，同时在非肿瘤细胞系中表现出耐药性。通过在 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，在联合治疗 2 周后以及用低剂量 Flavo 预处理 1 周后再联合治疗 2 周后，CPS49/flavo 给药均减少了肿瘤生长。 PTX 和 CPS49 组合并未显着减少 PC3 异种移植物中的肿瘤生长。来自 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的大面积坏死。 RT-qPCR 阵列包含来自暴露于 CPS49/flavo 组合的 PC3 细胞或 PC3 异种移植物的 23 个基因，表明这种处理关闭了与粘附、迁移或侵袭有关的几个基因的表达。总之，CPS49或flavopiridol的抗肿瘤活性通过这些化合物的组合和使用先前报道的一半剂量而得到改善。因此，CPS49-flavo 组合是 PCa 治疗的一种有前途的新替代方案。我们也有兴趣了解前列腺癌治疗方案的耐药机制。 Enzalutamide 是一种有效的第二代雄激素受体 (AR) 拮抗剂，具有治疗转移性去势抵抗性前列腺癌 (CRPC) 的活性。尽管恩杂鲁胺最初是有效的，但随着耐药性的出现，疾病不可避免地会发生进展。瘤内缺氧还与 CRPC 进展和治疗抵抗相关。鉴于 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，两个信号轴的双重靶向代表了一种有吸引力的治疗方法。在前列腺癌细胞系（LNCaP、22Rv1）中检查了 AR 和 HIF-1a 信号通路的串扰，并测量了雄激素和缺氧对 AR 依赖性和缺氧诱导的基因转录、蛋白质表达、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 相互作用的干扰剂）来实现的。在前列腺癌细胞中，AR 靶标（KLK3、FKBP5、TMPRSS2）的基因表达受到 HIF 信号传导的抑制；相反，特定的 HIF-1a 靶标表达是由二氢睾酮介导的 AR 信号传导诱导的。用 enzalutamide 或 HIF-1a 抑制剂处理 CRPC 细胞会减弱 AR 调节和 HIF-1a 介导的基因转录。恩杂鲁胺和 HIF-1a 抑制的组合比单独治疗更有效。同样，该组合还降低了血管内皮生长因子蛋白水平。 HIF-1a siRNA 通过增加恩杂鲁胺诱导的细胞凋亡，协同增强恩杂鲁胺对 LNCaP 和恩杂鲁胺耐药 22Rv1 细胞生长的抑制作用。总之，恩杂鲁胺与 HIF-1a 抑制的组合导致 AR 依赖性和基因特异性 HIF 依赖性表达和前列腺癌细胞生长的协同抑制。 Eovist (Gadoxetate) 增强 MRI 用于检测前列腺癌：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，即使在 ADT 环境下，也代表了前列腺肿瘤生长的可能机制，因为尽管血清睾酮浓度较低，但癌细胞仍能够清除额外的睾酮。目前没有能够评估 OATP1B3 转运蛋白状态的成像方法。这种方法对于根据 OATP1B3 状态对局部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。它适用于肝脏 T1 加权磁共振成像 (MRI) 中的静脉注射，以检测和表征患有已知或疑似局灶性肝病的成人的病变，特别是在肝细胞癌的诊断中。由于 Eovist 是一种低分子量显像剂，因此它可以快速增强所有血管器官和结构。然而，Eovist 不会被不表达 OATP1B3 的组织保留，因此在 20 分钟时，可以在表达 OATP1B3 的病变（持续增强）和不表达 OATP1B3 的病变（增强消退）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，可以观察前列腺癌中摄取时间的差异，以及这些差异是否与前列腺癌中 OATP1B3 表达相关，因此可以作为预测生物标志物。应计正在进行中。 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，从而阻止它们与其共同受体 Tie2 相互作用，并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针对 mCRPC 患者的联合靶向治疗的新策略。我们假设在 CYP17 抑制剂阿比特龙和泼尼松中添加曲巴尼布将增加初治 mCRPC 的中位无进展生存期。这项 2 期研究将评估接受 trebananib 加阿比特龙/泼尼松治疗的患者相对于单独阿比特龙/泼尼松治疗的患者的无进展生存期的治疗效果。我们还参与了该试验中的生物标志物研究。试验数据的分析正在进行中。卡博替尼 (XL184) 被开发为血管生成及其耐药机制的抑制剂。它是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，卡博替尼证明了对多种实体瘤类型的广泛抗肿瘤活性。卡博替尼是 CRPC 患者中缓解率最高的药物之一，疾病控制率（定义为 SD 或确认缓解）为 68%。我们参与了固定剂量多西他赛和泼尼松与卡博替尼联合以三个递增剂量进行的单臂 I 期研究，以确定卡博替尼与多西他赛和泼尼松联合的安全性，并确定与多西他赛联合的 II 期推荐剂量的最大耐受剂量。试验数据的分析正在进行中。