sunitinib

舒尼替尼
  • 文章类型: Journal Article
    近年来,舒尼替尼大大提高了透明细胞肾细胞癌(ccRCC)患者的生存率。然而,20-30%的治疗患者没有反应。为了鉴定与反应相关的miRNA和基因,比较了应答者和非应答者ccRCC患者的活检结果.使用整合的转录组学分析,我们鉴定了37个miRNAs和60个各自的靶基因,与NF-κB显著相关,PI3K-Akt和MAPK途径。我们验证了miRNA的表达(miR-223,miR-155,miR-200b,35例ccRCC患者的miR-130b)和靶基因(FLT1,PRDM1和SAV1)。高水平的miR-223和低水平的FLT1,SAV1和PRDM1与较差的总生存期(OS)相关。和组合的miR-223+SAV1水平区分应答者和非应答者(AUC=0.92)。使用170例ccRCC患者的免疫组织化学染色,VEGFR1(FLT1)表达与治疗反应相关,组织学分级和RECIST(实体瘤反应评估标准)评分,而SAV1和BLIMP1(PRDM1)与异时转移性疾病相关。使用原位杂交(ISH)检测miR-155,我们观察到无反应者的肿瘤细胞表达更高,和非肿瘤细胞表达随着组织学分级的增加。总之,我们使用整合的miRNA-靶基因分析进行的初步分析在ccRCC患者中发现了几种新的生物标志物,这些生物标志物肯定值得进一步研究.
    Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (miR-223, miR-155, miR-200b, miR-130b) and target genes (FLT1, PRDM1 and SAV1) in 35 ccRCC patients. High levels of miR-223 and low levels of FLT1, SAV1 and PRDM1 were associated with worse overall survival (OS), and combined miR-223 + SAV1 levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (FLT1) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (PRDM1) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect miR-155 we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.
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  • 文章类型: Journal Article
    背景:大多数胃肠道间质瘤(GIST)存在c-KIT或PDGFRA突变。酪氨酸激酶抑制剂(TKIs)的施用显著改善了患有GIST的患者的存活率。我们旨在评估台湾晚期或复发性GIST患者的临床结局。
    方法:纳入2010年至2020年确诊的患者。收集的数据包括基线特征,治疗模式,治疗结果,遗传畸变和生存状态。分析无进展生存期(PFS)和总生存期(OS)并用Kaplan-Meier法绘制。Cox回归分析影响生存的预后因素。
    结果:共纳入224例接受TKIs治疗的晚期或复发性GIST患者。所有患者均接受伊马替尼治疗。93例和42例患者接受舒尼替尼和瑞戈非尼治疗,分别。使用伊马替尼治疗的患者48个月PFS和OS分别为50.5%和79.5%,分别。在多变量Cox回归分析中,c-KIT外显子9和PDGFRA突变是PFS不良的预后因素,PDGFRA突变是伊马替尼治疗患者OS不良的预后因素。接受舒尼替尼治疗的患者的中位PFS为12.76个月(95%置信区间(CI),11.01-14.52)。具有c-KIT外显子9突变的患者比具有其他遗传畸变的患者具有更长的PFS。接受regorafenib治疗的患者的中位PFS为7.14个月(95%CI,3.39-10.89)。
    结论:我们展示了接受TKIs治疗的晚期GIST患者的真实临床结果,并确定了突变状态作为患者生存的独立预后因素。
    BACKGROUND: Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan.
    METHODS: Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival.
    RESULTS: A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89).
    CONCLUSIONS: We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.
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  • 文章类型: Journal Article
    目的:晚期肾透明细胞癌(ccRCC)严重影响患者的生命健康,但是这种疾病的有效治疗在临床上仍然缺乏。本研究探讨了纳武单抗联合卡博替尼与舒尼替尼治疗老年晚期ccRCC的疗效。
    方法:回顾性分析我院2020年1月至2022年1月216例老年晚期ccRCC患者的临床资料。根据不同的治疗方案,患者被分为卡博替尼组(n=111,接受纳武单抗和卡博替尼)和舒尼替尼组(n=105,接受纳武单抗和舒尼替尼).总生存时间,疾病控制率,健康状况,比较两组患者的不良事件发生率和预后风险.
    结果:卡博替尼组的总生存时间更长,癌症治疗功能评估-肾脏症状指数和EuroQol-五维度-三级问卷的疾病控制率和评分高于舒尼替尼组。卡博替尼组的不良事件发生率低于舒尼替尼组(p<0.001)。然而,两组间对预后风险的判断差异无统计学意义(p>0.05)。
    结论:纳武单抗联合卡博替尼治疗老年晚期ccRCC的效果优于纳武单抗联合舒尼替尼,不良反应少,安全性高。然而,研究结果需要进一步的临床研究来证实和推广。
    OBJECTIVE: Advanced clear cell renal cell carcinoma (ccRCC) seriously affects the life and health of patients, but effective treatment for this disease is still lacking in clinic. This study investigated the efficacy of nivolumab plus cabozantinib versus sunitinib in the treatment of elderly patients with advanced ccRCC.
    METHODS: The clinical data of 216 elderly patients with advanced ccRCC in our hospital from January 2020 to January 2022 were retrospectively analysed. On the basis of different treatment regimens, patients were divided into the cabozantinib group (n = 111, receiving nivolumab and cabozantinib) and the sunitinib group (n = 105, receiving nivolumab and sunitinib). The overall survival time, disease control rates, health status, incidence of adverse events and identification of prognostic risk were compared between the two groups.
    RESULTS: The cabozantinib group had higher overall survival time, disease control rate and scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index and EuroQol-Five Dimensions-Three Levels Questionnaire than the sunitinib group. The incidence of adverse events in the cabozantinib group was lower than that in the sunitinib group (p < 0.001). However, no difference existed in the identification of prognostic risk between the two groups (p > 0.05).
    CONCLUSIONS: The effect of nivolumab plus cabozantinib on the treatment of elderly patients with advanced ccRCC is better than that of nivolumab plus sunitinib, with fewer adverse reactions and higher safety. However, the research results require further clinical studies to confirm and promote.
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  • 文章类型: Case Reports
    一名62岁的男性出现肉眼血尿和右肾肿块,被转诊到我们的泌尿科。计算机断层扫描显示右肾肿块,肺部多发病变.他因高度怀疑的肾细胞癌伴肺转移(cT3aN0M1)接受了右肾切除术。病理诊断为肾透明细胞癌,pT1b.手术后,他接受了多种化疗方案,从干扰素α,多种酪氨酸激酶抑制剂,如索拉非尼,阿西替尼,帕唑帕尼和卡博替尼,依维莫司,还有Nivolumab,所有这些在诱导后都停止了,由于不良事件或进行性疾病。他最终接受了舒尼替尼作为第8行“最后一搏”治疗,导致显著的肿瘤缩小。在开始舒尼替尼给药后25个月没有观察到疾病进展。
    A 62-year-old male presenting with gross hematuria and right renal mass was referred to our Urology Department. Computed tomography revealed a right renal mass, with multiple pulmonary lesions. He underwent right nephrectomy for highly suspected renal cell carcinoma with pulmonary metastases (cT3aN0M1). The pathological diagnosis was clear cell renal cell carcinoma, pT1b. Following surgery, he was treated with multiple regimens of chemotherapy, ranging from interferon alpha, multiple tyrosine kinase inhibitors such as sorafenib, axitinib, pazopanib and cabozantinib, everolimus, and nivolumab, all of which were discontinued after its induction, either due to adverse events or progressive disease. He was finally administered Sunitinib as the 8th line \"last-ditch\" treatment, which resulted in significant tumor shrinkage. No disease progression has been observed 25 months after initiating sunitinib administration.
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  • 文章类型: Journal Article
    免疫检查点抑制剂(ICIs)的批准彻底改变了转移性肾细胞癌(RCC)的管理。引入几种基于ICI的组合作为受影响患者的新护理标准。尽管如此,抗血管生成酪氨酸激酶抑制剂(TKIs)的单一疗法,如帕唑帕尼或舒尼替尼,根据国际mRCC数据库联盟(IMDC)模型,仍是属于有利风险组的部分患者的一线治疗选择.TKI单药治疗后,到目前为止,主要的二线选择是ICI单药治疗与抗程序性死亡受体1(PD-1)纳武单抗,帕唑帕尼或舒尼替尼的预期临床结局相似,没有明确的选择TKI的适应症.此外,它们对随后的ICI治疗结果的影响尚未明确,yet.基于这些前提,我们研究了这些药物在体外和体内的免疫调节活性。TKIs诱导RCC细胞程序性死亡配体-1(PD-L1)表达和可溶性PD-L1释放,阻碍了T细胞的活化,减少细胞因子的产生和活化T细胞的比例。然而,在与外周血单核细胞(PBMC)和肿瘤细胞的同源共培养系统中,TKIs治疗后与抗PD-1抗体孵育显著恢复T细胞功能,增强对肿瘤细胞的细胞毒性作用。帕唑帕尼和舒尼替尼随后抗PD-1抗体在RCC同基因小鼠模型中产生对肿瘤生长的相当的抑制。我们的研究结果表明,帕唑帕尼和舒尼替尼,表现出相似的免疫调节作用,可能会对PD-1/PD-L1阻断的后续有效性产生相当的影响。
    The approval of immune checkpoint inhibitors (ICIs) has revolutionized the management of metastatic renal cell carcinoma (RCC), introducing several ICI-based combinations as the new standard of care for affected patients. Nonetheless, monotherapy with antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib or sunitinib, still represents a first-line treatment option for selected patients belonging to the favorable risk group according to the International mRCC Database Consortium (IMDC) model. After TKI monotherapy, the main second-line option is represented by ICI monotherapy with the anti-Programmed Death Receptor 1(PD-1) nivolumab. To date, the expected clinical outcomes are similar with pazopanib or sunitinib and there is no clear indication for selecting one TKI over the other. Moreover, their impact on subsequent ICI treatment outcomes is not well defined, yet. Based on these premises, we investigated the immunomodulatory activity of these drugs in vitro and in vivo.Both TKIs induced Programmed Cell Death Ligand-1 (PD-L1) expression and soluble PD-L1 release in RCC cells, and hampered T cell activation, reducing cytokine production and the proportion of activated T cells. Nevertheless, in a syngeneic co-culture system with peripheral blood mononuclear cells (PBMCs) and tumor cells, incubation with anti-PD-1 antibody following TKIs treatment significantly restored T cell function, potentiating the cytotoxic effects against tumor cells. Pazopanib and sunitinib followed by anti-PD-1 antibody produced a comparable inhibition of tumor growth in a RCC syngeneic mouse model. Our findings suggest that pazopanib and sunitinib, showing similar immunomodulatory effects, may have a comparable impact on the subsequent effectiveness of PD-1/PD-L1 blockade.
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  • 文章类型: Journal Article
    对酪氨酸激酶抑制剂(TKIs)的耐药性的发展是转移性肾细胞癌(mRCC)治疗失败的主要原因。更深入地了解与TKI抗性相关的代谢机制对于完善治疗策略至关重要。在这项研究中,我们通过将亲本Caki-1细胞系暴露于浓度增加的舒尼替尼和帕唑帕尼,确立了对舒尼替尼和帕唑帕尼的耐药性.使用基于核磁共振(NMR)的代谢组学方法研究了对舒尼汀和帕唑帕尼耐药的mRCC细胞的细胞内和细胞外代谢组。数据分析包括多变量和单变量方法,以及路径和网络分析。在这项研究中首次发现了对舒尼汀和帕唑帕尼耐药的RCC细胞中不同的代谢特征。在氨基酸中观察到一种常见的代谢重编程模式,甘油磷脂,和烟酸和烟酰胺代谢。舒尼替尼耐药细胞在参与抗氧化防御机制的代谢物中表现出明显的变化,而帕唑帕尼耐药细胞显示与能量途径相关的代谢物发生改变。舒尼替尼耐药的RCC细胞增殖能力增强,而帕唑帕尼耐药细胞似乎重组了能量代谢,并改变了与细胞死亡相关的途径。这些发现为通过代谢调节克服mRCC中的TKI抗性的新型治疗策略提供了潜在的靶标。
    The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper understanding of the metabolic mechanisms associated with TKI resistance is critical for refining therapeutic strategies. In this study, we established resistance to sunitinib and pazopanib by exposing a parental Caki-1 cell line to increasing concentrations of sunitinib and pazopanib. The intracellular and extracellular metabolome of sunitinib- and pazopanib-resistant mRCC cells were investigated using a nuclear magnetic resonance (NMR)-based metabolomics approach. Data analysis included multivariate and univariate methods, as well as pathway and network analyses. Distinct metabolic signatures in sunitinib- and pazopanib-resistant RCC cells were found for the first time in this study. A common metabolic reprogramming pattern was observed in amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolism. Sunitinib-resistant cells exhibited marked alterations in metabolites involved in antioxidant defence mechanisms, while pazopanib-resistant cells showed alterations in metabolites associated with energy pathways. Sunitinib-resistant RCC cells demonstrated an increased ability to proliferate, whereas pazopanib-resistant cells appeared to restructure their energy metabolism and undergo alterations in pathways associated with cell death. These findings provide potential targets for novel therapeutic strategies to overcome TKI resistance in mRCC through metabolic regulation.
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  • 文章类型: Journal Article
    疾病发作和进展的变异性是肌萎缩侧索硬化症(ALS)的标志,无论是零星的和遗传的形式。最近,我们发现SOD1-G93A转基因小鼠表达相同数量的突变SOD1,但具有不同的遗传背景,C57BL/6JOlaHsd和129S2/SvHsd,显示缓慢和快速的肌肉萎缩和疾病进展,分别。这里,我们研究了肌肉萎缩的不同分子机制。尽管两种菌株都显示出相似的去神经诱导的肌肉蛋白降解,只有快速进展的小鼠在腓肠肌萎缩之前表现出早期和持续的STAT3激活。因此,我们研究了舒尼替尼的治疗潜力,一种已知能抑制STAT3并预防癌症引起的肌肉萎缩的酪氨酸激酶抑制剂。尽管舒尼替尼治疗减少了腓肠肌和腰脊髓中STAT3的激活,它没有保留脊髓运动神经元,改善神经肌肉损伤,快速进展的SOD1-G93A小鼠的肌肉萎缩和疾病进展。因此,舒尼替尼在与肌肉萎缩相关的不同疾病中的效果不相同。此外,鉴于STAT3在神经肌肉系统的外周和中枢区室中的复杂作用,本研究表明,其广泛的抑制作用可能会导致相反的效果,最终阻止ALS的潜在积极治疗作用。
    Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.
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  • 文章类型: Case Reports
    药物性胸腔积液是渗出性胸腔积液的罕见原因之一,高度怀疑是早期诊断的必要条件。我们在此介绍一个30多岁的年轻男性的案例,舒尼替尼治疗的转移性胃肠道间质瘤的已知病例,出现右侧轻度胸腔积液。诊断性胸腔穿刺术显示积液为单形渗出物,腺苷脱氨酶低,在细胞病理学上没有恶性细胞。对比增强CT胸部显示4R站淋巴结肿大(LN),细胞学分析提示反应性淋巴增生。从右中叶取出的LN抽吸物和支气管肺泡灌洗的感染性检查为阴性。在系统地排除渗出性胸腔积液的常见原因后,舒尼替尼被认为是可能的原因,因此,扣留。停药3周后,重复进行胸部X光检查显示胸腔积液消退。
    Drug-induced pleural effusion is one of the rare causes of exudative pleural effusion and a high index of suspicion is necessary to lead to early diagnosis. We hereby present the case of a young male in his late 30s, known case of metastatic gastrointestinal stromal tumour on sunitinib therapy, who presented with right-sided mild pleural effusion. Diagnostic thoracentesis showed the effusion to be a monomorphic exudate with low adenosine deaminase, which was negative for malignant cells on cytopathology. A contrast-enhanced CT chest revealed an enlarged lymph node (LN) at the 4R station, cytological analysis of which was suggestive of reactive lymphoid hyperplasia. Infective workup of the LN aspirate and bronchoalveolar lavage taken from the right middle lobe was negative. After systematically excluding the usual causes of exudative pleural effusion, sunitinib was considered to be a possible cause and was, therefore, withheld. A repeat chest X-ray after 3 weeks of stopping the drug showed resolution of the pleural effusion.
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  • 文章类型: Journal Article
    背景:舒尼替尼是一种口服抗癌药物,被批准用于治疗胃肠道间质瘤(GIST)。先前的分析表明在标准剂量下存在暴露-反应关系,和药物暴露的最低目标水平已被定义,在上述水平上观察到更好的治疗结果。治疗药物监测(TDM)可以作为优化个体剂量的工具,针对持续给药的舒尼替尼谷浓度≥37.5ng/ml。尽管如此,目前缺乏TDM指导给药在临床终点的附加值数据.因此,我们从疗效和毒性方面评估了TDM在接受舒尼替尼治疗的晚期和转移性GIST患者中的疗效.
    方法:在中位无进展生存期(mPFS)和总生存期(mOS)方面,将TDM指导队列与非TDM指导队列进行比较。此外,比较了有和没有剂量限制性毒性(DLT)的患者之间的mPFS。前瞻性队列中的患者被纳入两项关于TDM指导给药的研究(DPOG-TDM研究和TUNE研究)。回顾性队列由荷兰GIST登记处未接受TDM指导给药的患者组成。
    结果:总计,51和106例患者被纳入TDM指导队列和非TDM指导队列。分别。在这两个队列之间没有观察到mPFS的统计学差异(39.4对46.9周,分别为;P=0.52)。经历舒尼替尼诱导的DLT的患者与未经历的患者相比,mPFS更长(51.9周与28.9周,分别为;P=0.002)。
    结论:我们的结果不支持在晚期/转移性GIST患者中常规使用TDM指导的舒尼替尼剂量优化来提高生存率。
    BACKGROUND: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure-response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity.
    METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing.
    RESULTS: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002).
    CONCLUSIONS: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.
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  • 文章类型: Journal Article
    目的:观察到糖尿病视网膜病变(DR)的病理性血管生成和血管不稳定性,糖尿病性黄斑水肿(DME),和湿性年龄相关性黄斑变性(wAMD)。许多受体酪氨酸激酶(RTKs)包括血管内皮生长因子受体(VEGFRs)有助于血管生成,而RTKTIE2对血管稳定性很重要。Pan-VEGFR酪氨酸激酶抑制剂(TKIs),如vorolanib,舒尼替尼,和阿西替尼比目前仅靶向一种或两种配体的抗体治疗具有治疗意义。这项研究比较了这些TKIs的抗血管生成潜力。
    方法:进行激酶HotSpot™测定以鉴定TKI抑制与血管生成和血管稳定性相关的RTK。测定每个TKI的VEGFRs和TIE2的半数最大抑制浓度(IC50)。使用人脐静脉内皮细胞发芽测定法研究了体外血管生成抑制,并使用绒毛尿囊膜测定法研究了体内血管生成。使用黑色素结合测定法评估黑色素结合。进行计算机建模以了解TIE2-阿西替尼复合物以及vorolanib和VEGFRs之间的相互作用。
    结果:沃罗拉尼,舒尼替尼,和阿西替尼抑制血管生成中感兴趣的RTK并表现出泛-VEGFR抑制。HotSpot™测定和TIE2IC50值显示只有阿西替尼有效抑制TIE2(高达89%)。所有三种TKIs均在体外有效抑制血管生成。在体内,TKI在抑制VEGF诱导的血管生成方面比抗VEGF抗体贝伐单抗更有效。在三个TKIs中,只有舒尼替尼结合黑色素。TKIs的分类和与VEGFR的结合不同,这很重要,因为II型抑制剂比I型TKIs具有更大的选择性。
    结论:沃罗拉尼,舒尼替尼,和阿西替尼表现出泛VEGFR抑制作用,并抑制与病理性血管生成相关的RTK。在三个TKIs中,只有阿西替尼才能有效抑制TIE2,这是一种不希望的性状,因为TIE2对血管稳定性至关重要。研究结果支持使用vorolanib治疗性抑制DR中观察到的血管生成,DME,WAMD。
    OBJECTIVE: Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration (wAMD). Many receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFRs) contribute to angiogenesis, whereas the RTK TIE2 is important for vascular stability. Pan-VEGFR tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib are of therapeutic interest over current antibody treatments that target only one or two ligands. This study compared the anti-angiogenic potential of these TKIs.
    METHODS: A kinase HotSpot™ assay was conducted to identify TKIs inhibiting RTKs associated with angiogenesis and vascular stability. Half-maximal inhibitory concentration (IC50) for VEGFRs and TIE2 was determined for each TKI. In vitro angiogenesis inhibition was investigated using a human umbilical vein endothelial cell sprouting assay, and in vivo angiogenesis was studied using the chorioallantoic membrane assay. Melanin binding was assessed using a melanin-binding assay. Computer modeling was conducted to understand the TIE2-axitinib complex as well as interactions between vorolanib and VEGFRs.
    RESULTS: Vorolanib, sunitinib, and axitinib inhibited RTKs of interest in angiogenesis and exhibited pan-VEGFR inhibition. HotSpot™ assay and TIE2 IC50 values showed that only axitinib potently inhibited TIE2 (up to 89%). All three TKIs effectively inhibited angiogenesis in vitro. In vivo, TKIs were more effective at inhibiting VEGF-induced angiogenesis than the anti-VEGF antibody bevacizumab. Of the three TKIs, only sunitinib bound melanin. TKIs differ in their classification and binding to VEGFRs, which is important because type II inhibitors have greater selectivity than type I TKIs.
    CONCLUSIONS: Vorolanib, sunitinib, and axitinib exhibited pan-VEGFR inhibition and inhibited RTKs associated with pathological angiogenesis. Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability. The findings support the use of vorolanib for therapeutic inhibition of angiogenesis observed in DR, DME, and wAMD.
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