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布后，多西他赛化疗成为患有耐castrate的前列腺癌（MCRPC）男性的护理标准。在2010年之前，多西他赛和泼尼松是唯一证明MCRPC患者生存益处的治疗方法。 MCRPC治疗的最新进展已彻底改变了治疗算法。尽管它们对总体生存（OS）的影响，但Sipuleucel-T和Alpharadin对有症状的患者或内脏转移患者的影响不明。阿比罗酮和enzalutamide具有有利的毒性谱，但是它们具有抗药性机制，可能会降低顺序使用的益处。因此，这些治疗对MCRPC的好处仍然有限。现在，试验专注于通过将其与新型生物学剂相结合来提高多西他赛的功效。在临床前和临床环境中，几种新的基于多西他赛的组合和新型药物都在评估中，结果有令人鼓舞的结果。我们研究了新药组合对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-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).我们发现CPS49在人PCA细胞系中增强了Flavo或PTX细胞毒性，同时在非肿瘤细胞系中表现出抗性。 NU/NU小鼠中人类前列腺癌PC3细胞产生的异种移植物表明，在共同治疗2周后，CPS49/Flavo给药减少了肿瘤的生长，并在预处理1周后使用低剂量的Flavo进行了预处理，然后进行了2周的共同处理。 PTX和CPS49组合并未显着降低PC3异种移植物中的肿瘤生长。 CPS49/Flavo组合的异种移植PC3肿瘤样品的组织学分析显示，该治疗诱导的坏死区域。 RT-QPCR阵列中包含来自PC3细胞或PC3异种移植物的23个基因，暴露于CPS49/Flavo组合表明，这种处理可以关闭与粘附，迁移或侵袭有关的几个基因的表达。总而言之，通过这些化合物的组合并使用先前报道的一半剂量，可以改善CPS49或黄叶肽的抗肿瘤活性。因此，CPS49-Flavo组合是PCA治疗的有前途的新替代方法。我们也有兴趣了解前列腺癌方案的抗性机制。恩扎拉胺是一种有效的第二代雄激素受体（AR）拮抗剂，其活性在转移性castrate的前列腺癌（CRPC）中。尽管恩扎拉胺最初是有效的，但随着抗药性的出现，疾病的进展不可避免地随之而来。肿瘤内缺氧也与CRPC进展和耐药性有关。鉴于AR和缺氧诱导因子-1α（HIF-1A）都是这些过程的关键调节剂，因此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，测量了雄激素和缺氧对AR依赖性和低氧诱导基因转录，蛋白质表达，细胞增殖和凋亡的影响。 HIF-1A抑制是通过siRNA静音HIF-1A或通过chetomin的HIF-1A-1A-P300相互作用来实现的。在前列腺癌细胞中，AR靶标（KLK3，FKBP5，TMPRSS2）的基因表达被HIF信号抑制。相反，二氢睾丸激素介导的AR信号传导诱导了特定的HIF-1A靶表达。用enzalutamide或HIF-1A抑制作用治疗CRPC细胞会减弱AR调节和HIF-1A介导的基因转录。 enzalutamide和HIF-1A抑制作用的组合比单独使用任何一种治疗更有效。同样，该组合还降低了血管内皮生长因子蛋白水平。 HIF-1A siRNA协同增强了enzalutamide对LNCAP和Enzalutamide耐药22RV1细胞中恩扎拉塔酰胺诱导的细胞凋亡的抑制作用。总之，恩扎拉氨酰胺与HIF-1A抑制作用的组合导致对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作用。 EOVIST（GADOXETATE）增强了预测前列腺癌的MRI：有机阴离子转运蛋白多肽1B3（OATP1B3）是一种睾丸激素转运蛋白在前列腺肿瘤中从头表达的转运蛋白，即使在癌细胞的能力下，在癌细胞的设置下，即使在癌症的能力下，也代表了前列腺肿瘤生长的可能机制。目前没有能够评估OATP1B3转运蛋白的状态的当前成像方法。这种方法对于通过局部和转移性疾病的OATP1B3状态将患者的危险因素分层可能很重要。 EOVIST是一种基于Gadolinium的对比剂，在2008年获得FDA的批准。它在肝脏的T1加权磁共振成像（MRI）中用于静脉内使用，以检测和表征患有已知或可疑局灶性肝病的成人病变，尤其是在诊断出肝细胞癌诊断的诊断中。由于EOVIST是一种低分子量成像剂，因此迅速增强了所有血管器官和结构。然而，非oatp1b3表达组织不会保留EOVIST，因此在20分钟时，可以在OATP1B3表达病变（持续增强）和非AITP1B3表达病变（增强量）之间建立相关性。因此，我们正在患有局部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，以观察前列腺癌的摄取时间差异，以及这些差异是否与前列腺癌中的OATP1B3表达相关，因此可能用作预测性的生物标志物。应计正在进行。 Trebananib（AMG386）是一种新型的肽-FC融合蛋白，可隔离Angiopoeitin 1和Angiopoeitin 2，从而防止其与共同受体TIE2的相互作用，并抑制肿瘤内皮细胞增殖和肿瘤生长。对雄激素和血管生成轴的双重抑制代表了针对MCRPC患者组合靶向治疗的新型策略。我们假设将Trebananib添加到CYP17抑制剂阿比罗酮和泼尼松将增加化学疗法 - 不接受MCRPC中的中位进展生存期。这项2阶段研究将评估用Trebananib和Abiraterone/泼尼松相对于阿比罗酮/泼尼松治疗的患者，通过无进展生存率来评估治疗效果。我们还参与了该试验的生物标志物研究。试验数据的分析正在进行中。 Cabozantinib（XL184）作为血管生成及其耐药机制的抑制剂开发。它是包括C MET，VEGFR2和RET在内的多种受体酪氨酸激酶的抑制剂。在单药临床研究中，Cabozantinib证明了许多实体瘤类型的广泛的抗肿瘤活性。 Cabozantinib在CRPC患者中产生了最高的疾病控制率（定义为SD或已确认反应）的反应率之一。我们参与了一项单臂I期研究，将固定剂量的多西他赛和泼尼松与Cabozantinib结合使用，以三种不断升级的剂量结合使用，也确定了Cabozantinib与多西他赛和泼尼松结合使用的安全性，并确定最大耐受剂量作为建议的II期剂量，并与ICETAXEL结合使用。试验数据的分析正在进行中。