Regorafenib联合TAS102新策略治疗肝细胞癌的研究

背景与目的：瑞格菲尼（regorafenib,REG）和TAS102是治疗消化道肿瘤的新型药物。嘧啶类药物5-氟尿嘧啶（5-fluorouracil,5-FU）联合REG可抑制多药耐药转移性结肠癌的进展。肿瘤干细胞（cancer stem cell,CSC）决定肿瘤的自我更新,异质性及治疗耐受等,靶向CSC为治愈肿瘤提供了可能途径。探讨REG联合TAS102治疗肝细胞癌（hepatocellular carcinoma,HCC）的联合效应及潜在机制。方法：以人HepG2、Huh7和SK-Hep1肝癌细胞系为实验对象。REG和TAS102单药或联合处理肝癌细胞及荷瘤动物。采用细胞计数试剂盒（cell counting kit-8,CCK-8）检测肝癌细胞活力;流式细胞术分析肝癌细胞中CD133阳性细胞亚群比例;采用蛋白质印迹法（Western blot）分析不同药物处理后肝癌细胞中蛋白表达差异;含不同药物的干细胞培养基培养肝癌干细胞球（HCC sphere）;荷瘤动物实验评估药物联合治疗效果。结果：REG及TAS102单药显著抑制肝癌细胞活力。TAS102联合使用减低REG单药时诱导增加的CD133阳性细胞亚群比例及干细胞标志分子SRY相关的高迁移率族盒蛋白-2（SRY-related high mobility group box protein-2,SOX2）和乙醛脱氢酶1A（aldehyde dehydrogenase 1A,ALDH1A）的蛋白水平。同时REG的联合使用下调TAS102单药处理时诱导活化的抗凋亡蛋白髓细胞白血病-1蛋白（myeloid cell leukemia-1,MCL1）信号。REG联合TAS102显著抑制了HCC sphere的形成。动物实验证实REG联合TAS102显著抑制肝癌瘤体的生长。结论：REG联合TAS102通过调控肝癌细胞的干细胞性及抗凋亡信号,发挥联合用药增强抗HCC的活性,为临床治疗难治性HCC提供了一种新的治疗策略。     

Tolerance and Efficacy of Regorafenib according to UGT Pharmacogenetical Status in the Treatment of Metastatic Refractory Colorectal Cancer

Introduction: Regorafenib is a multi tyrosin-kinase inhibitor prescribed in metastatic refractory colorectal cancer treatment. Its toxicity is significant but inconstant. The metabolism of regorafenib includes oxydation via cytochrome P3A4, then glucuroconjugation. A pharmacogenetical approach of mutational status of Uridine-Diphospho-Glucuronosyltransfersase (UDP-glucuronosyl-transferase, UGT) could be a strategy to optimise the use of regorafenib. Patients and Method: This is a restrospective, unicentric study. All adult patients treated with regorafenib for a metastatic colorectal cancer in our center between 2013 and 2017 were analysed. UGT1A1 polypmorphism was previously researched in the laboratory after written informed consent. Results: Thirty-five patients received regorafenib during the study period. A TA repetition in UGT1A1 gene was present for 16 patients including two Gilbert syndrome. There were no more adverse events on patients with a heterozygous TA repetition or with a Gilbert syndrome compared with patients without UGT polymorphism, whatever the dosage at initiation of regorafenib. Adverse events grade 2 or superior, and grade 3 or superior tended to be more noticeable when the starting dose was 120 or 160 mg per day compared to 80 mg per day, but not statistically significant. No difference was observed on progression-free survival neither depending on UGT status nor depending on initating dose of regorafenib. Conclusion: This is a preliminary study evaluating safety of regorafenib according to UGT1A1 polymorphism. Larger and prospective studies are needed to evaluate dose-escalation strategy in patients with variable activity of glucuroconidation, especially Gilbert syndrome, or with abnormalities in other UGT enzymes such as UGT1A9.     

Resistance to multikinase inhibitor actions mediated by insulin like growth factor-1

Background

Blood platelet numbers are correlated with growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) both stimulated HCC cell growth and migration, and antagonized the growth-inhibitory and apoptotic effects of Regorafenib, multikinase growth inhibitor, on HCC cell lines. We evaluated the effects of human insulin-like growth factor-1 (IGF1), a mitogen contained in platelets, on the Regorafenib-mediated growth inhibition.

Methods

An Elisa kit was used to evaluate hPL IGF1 concentrations. The effects of IGF1 on cell proliferation were assessed with MTT assay and analysis of cell cycle progression. Apoptosis assays, scratch assay and Transwell assay were performed to measure apoptosis, cell migration and invasion respectively. Western blots were performed by standard protocols.

Results

IGF1 antagonized growth inhibition exerted by Regorafenib on HCC cell lines. Moreover the mitogen blocked Regorafenib-induced apoptosis and decreased the rate of cell migration and invasion. The IGF1 effects were in turn antagonized by actions of a potent IGF1 receptor inhibitor, GSK1838705A, showing that the IGF1 receptor was involved in the mechanisms of IGF1-mediated blocking of Regorafenib action. GSK1838705A also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that IGF1 was an important component of hPL actions.

Conclusions

These results show that IGF1 antagonized Regorafenib-mediated growth, migration and invasion inhibition, as well as the drug-mediated induction of apoptosis in HCC cells and reinforce the idea that microenvironmental factors can influence cancer drug actions.     

瑞格非尼治疗转移复发性结直肠癌的研究进展

目前,针对特异性分子靶点的靶向药物治疗已成为转移复发性结直肠癌（mCRC）治疗的新方向。2012年瑞格非尼被美国FDA批准用于mCRC患者,瑞格非尼是一种新型小分子多激酶抑制剂,能阻断多种促进肿瘤生长的激酶。多项临床研究结果显示瑞格非尼能显著延长mCRC患者的生存期。本文结合国内外最新研究报道,对瑞格非尼治疗mCRC的研究进展作一综述。     

新型口服多激酶抑制剂瑞戈非尼治疗癌症的研究进展

分子靶向治疗是近年来肿瘤治疗领域的研究热点。由于大多数肿瘤的生物学行为由多个信号传导通路共同发挥作用,故普遍认为针对多靶点进行分子靶向治疗有可能获得更好的疗效。瑞戈非尼（Regorafenib,BAY 73-4506）是一种新型的口服多靶点磷酸激酶抑制剂,能阻断肿瘤细胞增殖、抑制肿瘤血管生成、调控肿瘤微环境,具有良好的抗肿瘤活性。2012年9月,瑞戈非尼获得美国食品药品监督管理局（FDA）批准,用于治疗既往接受过标准治疗的转移性结直肠癌。2013年2月,瑞戈非尼获批准用于进展期胃肠间质瘤。目前已完成了两项瑞戈非尼大型随机国际性多中心Ⅲ期临床试验,分别是针对转移性结直肠癌和胃肠间质瘤。CORRECT研究首次证实,小分子激酶抑制剂瑞戈非尼在标准治疗失败后的转移性结直肠癌中能达到总生存获益。GRID研究提示,对于伊马替尼和舒尼替尼治疗后疾病进展的转移性或不可切除胃肠间质瘤患者,瑞戈非尼较安慰剂可显著改善无进展生存期,为这一难治性患者群带来获益。瑞戈非尼的不良反应与其他类似的口服多靶点激酶抑制剂相似,大多数不良反应为轻、中度,可以通过临床处理得到控制。瑞戈非尼单药或与标准化疗药物联合治疗其他恶性肿瘤的临床研究目前正在积极开展中。     

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand–Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib

Background

The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib.

Role of Predictive Value of the Modified Glasgow Prognostic Score for Later-line Chemotherapy in Patients With Metastatic Colorectal Cancer

Background

Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated.

瑞戈非尼联合XELOX化疗方案治疗结直肠癌的临床研究

目的 探究瑞戈非尼联合XELOX化疗方案治疗结直肠癌疗效及对血管新生指标、肿瘤免疫逃逸的影响。方法 选取2018年1月—2022年1月泸州市人民医院收治的80例结直肠癌患者,随机分为对照组和治疗组,每组各40例。对照组采用XELOX方案治疗,第1天静脉滴注注射用奥沙利铂130 mg/m²;第1～14天,口服卡培他滨片1 000 mg/m²,2次/d;21 d为1个周期。治疗组在对照组基础上口服瑞戈非尼片,160 mg/次,1次/d,用药21 d停用7 d,28 d为1个周期。病情进展或无法耐受停止用药。观察两组患者疾病控制率,比较治疗前后两组患者血清癌胚抗原（CEA）、大肠特异性抗原-2（CCSA-2）、糖类抗原19-9（CA19-9）、血管内皮生长因子（VEGF）、转化生长因子-β（TGF-β）、程序性死亡分子-1（PD-1）、程序性死亡分子配体-1（PD-L1）水平,及生存质量。结果 治疗后,治疗组疾病控制率（77.50%）较对照组（55.00%）明显升高（P<0.05）。治疗后,两组CA19-9、CCSA-2、CEA、TGF-β、VEGF、PD-1和PD-L1水平较治疗前明显降低（P<0.05）,且治疗组比对照组降低更明显（P<0.05）。治疗3个周期后,治疗组生存质量明显优于对照组（P<0.05）。结论 瑞戈非尼联合XELOX方案治疗结直肠癌效果显著,可有效抑制血管新生,改善肿瘤细胞免疫逃逸,从而使肿瘤标志物水平降低,提高生存质量。     

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.