多靶点酪氨酸激酶抑制剂舒尼替尼的研究进展

近年来各种酪氨酸激酶抑制剂不断涌现,以酪氨酸激酶抑制剂为代表的分子靶向治疗已成为抗肿瘤研究的热点.舒尼替尼(sunitinib,商品名Sutent)是一种小分子多靶点酪氨酸激酶抑制剂,对血小板衍生生长因子受体(PDGFR)、血管内皮生长因子受体(VEGFR)、干细胞因子受体(C-Kit)等多种受体酪氨酸激酶具有抑制作用,已于2006年1月被美国FDA批准用于临床上晚期肾细胞癌(RCC)和对伊马替尼(ima-tinib)耐药和(或)治疗失败的胃肠道间质瘤(GIST)的治疗,并在其他多种肿瘤的临床试验中也显示显著抗肿瘤活性,文中综述了该药的临床前研究及临床研究进展.     

Pharmacogenetics of tyrosine kinase inhibitors in gastrointestinal stromal tumor and chronic myeloid leukemia

Introduction: Gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML) are two tumor types deeply different from each other. Despite the differences, these disorders share treatment with tyrosine kinase inhibitor imatinib. Despite the success of imatinib, the response rates vary among different individuals and pharmacogenetics may play an important role in the final clinical outcome.

Areas covered: In this review, the authors provide an overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST and CML treatment efficacy and toxicity.

Expert opinion: So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, the data are not yet conclusive enough to translate pharmacogenetic tests in clinical practice. In this context, the major obstacles to pharmacogenetic test validation are represented by the small sample size of most studies, ethnicity and population admixture as confounding source, and uncertainty related to genetic variants analyzed. In conclusion, a combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.     

Current evidence on thyroid related adverse events in patients treated with protein tyrosine kinase inhibitors

Abstract

Tyrosine kinase inhibitors (TKI) are gaining more ground in oncology, they are widely used in the treatment of multiple types of cancers; still important side effects limit their efficacy. The aim of this study is to evaluate the existing medical literature on TKI induced thyroid dysfunction, to assess the adverse effects of targeted therapy on thyroid function in oncological patients and to evaluate the effects of thyroid dysfunction on disease prognosis. We included in this review 22 original studies published between 2010 and 2019. We used the PubMed database to search for articles upon the development of hypothyroidism and hyperthyroidism in TKI treated patients. After a careful review of the existing literature, we selected the relevant studies and cross-referenced the bibliography of each paper. A number of 1641 patients were included in our review. We found that thyroid dysfunction is not a rare side effect of TKI treatment, approximately 33% of the total number of patients presented clinical hypothyroidism. We also studied the necessity of thyroid hormone substitution treatment, a quarter of evaluated patients needed substitution therapy. Multiple studies showed that there is a link between a patient developing hypothyroidism and progression free survival. Hypothyroidism is a frequent side effect of TKI treatment, which affects the quality of life, sometimes even determines physicians to stop TKI treatment altogether. Our study underlines the necessity of TSH baseline testing and monitoring in patients treated with TKI agents.     

胃肠间质瘤45例临床诊治体会

目的探讨胃肠道间质瘤（GIST）的诊断和治疗。方法对我院2001年12月至2006年5月收治的45例临床资料完整GIST患者的临床表现、治疗方法及病理结果进行回顾性分析。结果45例均行手术治疗,其中良性5例（11．1％）,潜在恶性13例（28．9％）,恶性27例（60．0％）,免疫组织化学Ⅲ型跨膜蛋白酪氨酸激酶生长因子受体蛋白（CD）117、CD34阳性表达均为24例（93．3％）。23例获随访,随访时间5～64个月,其中3例死亡,1例出现肝转移。结论GIST缺乏特异性临床表现,术前确诊率低,多以黑便、腹痛和腹部肿块为主要症状;治疗上以手术治疗为主,术后辅以酪氨酸激酶抑制剂治疗具有较好疗效。     

酪氨酸激酶抑制剂治疗慢性粒细胞白血病的不良反应及处理的研究进展

酪氨酸激酶抑制剂(TKI)抑制BCR-ABL基因,改善慢性粒细胞白血病(CML)患者长期生存,与正常人寿命无差异.CML患者使用TKI早期出现不良反应较轻,可对症处理或自行恢复,较严重时可考虑更换TKI.国内报道TKI长期使用的安全性问题多表现在血液学不良反应,其他不良反应文献报道少见,本文通过查询国内外文献,对TKI...     

Emerging drugs for the treatment of gastrointestinal stromal tumour

Introduction: Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for patients with gastrointestinal stromal tumors (GIST). Unfortunately, resistance to the currently approved TKIs poses a huge challenge, and patients are in need of additional therapeutic options. Fortunately, many novel therapeutic approaches are being tested in treatment of GIST to overcome resistance to the approved TKIs

Areas covered: We performed an extensive literature (PUBMED) search to identify emerging drugs being tested in treatment of GIST in early phase clinical trials. We discuss recent ongoing research and emerging novel inhibitors of KIT and PDGFRA receptors, inhibitors in downstream signaling pathways (mTOR and PIK3 inhibitors), inhibitors of other potential targets including ETV1/MEK, MET, FGFR, IGF1R, histone deacetylase inhibitors, heat shock protein 90 inhibitors, cyclin-dependent kinase inhibitors and immune checkpoint inhibitors in treatment of GIST

Expert opinion: Multiple agents are under evaluation; those that benefit GIST patients with imatinib resistant mutations, or those with benefit in patients refractory to approved agents are most likely to be developed in this disease. The role of immunotherapy for GIST is still investigational.     

A safety evaluation of imatinib mesylate in the treatment of gastrointestinal stromal tumor

ABSTRACT

Introduction: For the last 15 years, imatinib mesylate has been the first line treatment of choice for advanced (metastatic) GIST.

Areas covered: This review describes key efficacy data on imatinib for the treatment of GIST, and focuses on safety and tolerability of imatinib, with emphasis on common adverse events management and long term toxicity profile.

Expert opinion: Imatinib has been the standard of care for metastatic GIST and probably will continue to be so for the next few years. Still, despite dramatic responses initially, imatinib drug resistance continues to be the major factor for treatment discontinuation. The toxicity profile of imatinib has been well characterized, and although the majority of patients experience an adverse event during treatment with imatinib, these side effects are usually mild and manageable, with the majority of patients continuing treatment uninterruptedly. Early concerns regarding imatinib related cardiotoxicity in GIST have not been confirmed in large prospective randomized trials, with reports indicating a low incidence of approximately 0.2%-0.4%. Future strategies for treatment of imatinib resistant GIST will probably include novel tyrosine kinase inhibitors, combination therapies or immunotherapy.     

中国胃肠间质瘤患者服用伊马替尼稳态谷浓度的初步分析

目的：研究中国胃肠间质瘤（gastrointestinal stromal tumor,GIST）患者服用伊马替尼稳态浓度的分布情况,为开展伊马替尼治疗药物浓度监测和个体化治疗提供依据。方法：收集服用甲磺酸伊马替尼达稳态（29 d）的GIST患者血浆,HPLC-MS/MS法检测血浆伊马替尼浓度。分析不同剂量伊马替尼血药浓度的差异以及个体间和个体内变异。结果：共收集88例GIST患者的154份血浆样本。服用伊马替尼600 mg·d^-1（n=4）、400 mg·d^-1（n=81）、300 mg·d^-1（n=1）、200 mg·d^-1（n=2）的患者血药浓度分别为（3 032.50±679.94）ng·mL^-1,（1 525.14±599.87）ng·mL^-1,1 155 ng·mL^-1,（655.57±21.92）ng·mL^-1。伊马替尼个体间变异39.57%,个体内变异为22.32%。单变量分析显示,伊马替尼血药浓度与性别、年龄、肿瘤切除部位以及是否转移无关。结论：中国GIST患者服用伊马替尼血药浓度个体差异较大,十分有必要进行血药浓度监测。     

表皮生长因子受体多态性对酪氨酸激酶抑制剂药效学影响的研究进展

目前表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂（TKI）在治疗非小细胞肺癌中得到广泛应用。本文回顾了影响酪氨酸激酶抑制剂药效的EGFR基因多态性以及相关的EGFR基因突变位点对酪氨酸激酶抑制剂吉非替尼治疗非小细胞肺癌的药效发挥产生何种影响的相关研究,说明EGFR的基因多态性对酪氨酸激酶抑制剂的药效发挥产生了重要的作用。     

酪氨酸激酶抑制剂的不良反应

分子靶向药物用于治疗恶性肿瘤效果显著,已成为抗肿瘤治疗的一个重要手段。其中酪氨酸激酶抑制剂已广泛运用于慢性髓系白血病、非小细胞肺癌、胃肠道间质瘤和肾细胞癌等的治疗,发挥着高效、低毒的抗肿瘤作用。但在临床使用过程中常可引起皮疹、水肿、腹泻等不良反应,涉及皮肤、消化、呼吸、血液等多个系统,严重者可危及生命,故在临床使用过程中应充分关注不良反应的发生和处理。本文对国内批准上市的酪氨酸激酶抑制剂致各个系统的不良反应进行综述,为临床治疗提供参考。     

蛋白酪氨酸激酶抑制剂的研究进展

目的综述蛋白酪氨酸激酶(protein tyrosine kinase,PTK)抑制剂类抗肿瘤药物的研究进展。方法根据已报道的PTK抑制剂的相关文献,将其分为国外已经上市、国外处于临床研究和我国自主研发的PTK抑制剂进行具体介绍。结果 PTK在细胞内的信号转导中起着重要的作用,与肿瘤细胞的生长、增殖、分化和凋亡密切相关,目前已经有多种结构的PTK抑制剂类抗肿瘤药物上市或进入临床研究。结论随着PTK的作用机制及构效关系研究的不断深入,该类药物终将成为治疗肿瘤的有效药物。     

Is there truly an increase in risk of cardiovascular and hematological adverse events with vascular endothelial growth factor receptor tyrosine kinase inhibitors?

ABSTRACT

Objectives: Recent studies have shown an increase risk of cardiovascular and hematological adverse events associated with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). The authors hypothesize that the original studies may have produced exaggerated results because of the small baseline risks involved.

Methods: A meta-analysis that included 71 trials, 8 different VEGFR-TKIs, and 11 adverse events were re-analyzed. The outcome of interest was re-defined as the complementary outcome (i.e. remaining free of an adverse event). The inverse variance heterogeneity model was used to pool the effect size.

Results: VEGFR-TKIs decreased the risk of remaining free of hypertension by 7% (RR 0.93; 95%CI:0.88–0.97). Specific VEGFR-TKIs; pazopanib, regorafenib, and nintedanib were associated with a decrease risk of remaining free of an arterial thrombotic event (RR 0.96; 95%CI:0.93–0.99), thrombocytopenia (RR 0.91; 95%CI:0.89–0.93), and bleeding (RR 0.96; 95%CI:0.93–0.99) respectively. VEGFR-TKIs were not associated with the thrombotic event, myocardial infarction, stroke, venous thrombotic event, pulmonary embolism, left ventricular dysfunction, or QTc interval prolongation.

Conclusion: VEGFR-TKIs are associated with a small increase in the risk of patients developing hypertension, arterial thrombotic events, thrombocytopenia, and bleeding. Previous studies overestimated the actual risk associated with VEGFR-TKIs by analyzing the outcome with the lower baseline risk.     

Imatinib mesilate for the treatment of gastrointestinal stromal tumour

Background: The molecular hallmark of gastrointestinal stromal tumours (GISTs), the mutation of the KIT gene, was discovered 10 years ago. GISTs have since been recognized as separate pathological entities among sarcomas, and have become a model for targeted treatment of solid tumours. Imatinib mesilate, which was approved in 2002 for the treatment of patients with advanced GIST, has dramatically changed the course of the disease. Objective: This article will focus on the development of imatinib mesilate in the treatment of patients with GIST. Methods: A Pubmed search was performed using the keywords ‘imatinib’, ‘gastrointestinal stromal’, ‘GIST’, ‘KIT’ and ‘PDGFR’. Websites of the American Society of Clinical Oncology and the European Society of Medical Oncology were searched for data reported in abstract form at recent symposiums. Personal communications from opinion leaders were sought for additional information that might be relevant. Results: Imatinib has changed the clinical course of patients with advanced GISTs and further development in the adjuvant setting as well as prospective assessment of predictive factors are the current focus of ongoing research.     

Preclinical analysis of the analinoquinazoline AG1478, a specific small molecule inhibitor of EGF receptor tyrosine kinase

The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30-48 min). The linear relationship between dose and AUC(0-->infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.delta2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.     

Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia

Aberrant signal transduction by mutant or overexpressed protein kinases has emerged as a promising target for treatment of acute myeloid leukemia (AML). We here present a novel low molecular weight kinase inhibitor, AKN-032, targeting the FMS-like tyrosine kinase 3 (FLT3) and discovered in a new type of screening funnel combining the target therapy approach with sequential cellular screens. AKN-032 was identified among 150 selected hits from three different high throughput kinase screens. Further characterization showed inhibitory activity on FLT3 enzyme with an IC₅₀ of 70 nM. Western blot analysis revealed reduced autophosphorylation of the FLT3-receptor in AML cell line MV4-11 cells after exposure to AKN-032. Flow cytometry disclosed cytotoxic activity against MV4-11, but not against non-malignant 3T3-L1 fibroblast cells. Using a fluorometric microculture cytotoxicity assay, AKN-032 was tested against 15 cell lines and displayed a potent cytotoxic activity in AML cell lines MV4-11 (IC₅₀ = 0.4 μM) and Kasumi-1 (IC₅₀ = 2.3 μM). AKN-032 was also highly cytotoxic in tumor cells from AML patients in vitro. Furthermore, AKN-032 demonstrated significant antileukemic effect in a relatively resistant in vivo hollow fiber mouse model. No major toxicity was observed in the animals. In conclusion, AKN-032 is a promising new kinase inhibitor with significant in vivo and in vitro activity in AML. Results from the hollow fiber mouse assay suggest a favorable toxicity profile. Future studies will focus on pharmacokinetic properties, toxicity as well as further clarifying the mechanisms of action of AKN-032 in AML.     

The safety of regorafenib for the treatment of gastrointestinal stromal tumors

Introduction: The management of gastrointestinal stromal tumors (GIST) evolved due to effective molecularly targeted therapy with imatinib and sunitinib which are used first- and second-line, respectively. However, due to the development of resistance to those drugs in the majority of patients, the need for third-line therapy arose.

Areas covered: Regorafenib, an oral multitargeted inhibitor with activity against multiple kinases including KIT, RET, RAF1, BRAF, angiogenesis (VEGFR, TIE-2) and those involved in tumor microenvironment (PDGFR and FGFR) was introduced after the successful Phase III GRID (GIST – Regorafenib In progressive Disease) clinical trial. This study showed significant improvement in progression-free survival for patients receiving regorafenib compared to placebo (4.8 months vs 0.9 months). The treatment was reasonably well tolerated, with arterial hypertension, hand-foot syndrome, diarrhea being the most common grade ≥3 adverse events, which could be managed by dose reduction and supportive treatment. The aim of this paper is to describe, assess and advise on the safety of regorafenib as third-line therapy in GIST.

Expert opinion: Regorafenib has demonstrated clinical benefit in GIST patients after progression on prior treatment with at least imatinib/sunitinib and currently it is the approved standard third-line option in therapy of advanced GIST. The safety profile is similar to other multikinase inhibitors with anti-VEGFR activity and is manageable.     

胃肠道间质瘤中干细胞因子的表达及与其细胞增殖的关系

目的研究干细胞因子(SCF)在胃肠道间质瘤(GIST)中的表达,及其与GIST细胞增殖的关系。方法收集GIST标本共68例,包括石蜡组织47例和新鲜组织21例,免疫组织化学及Western blot方法检测GIST组织中SCF表达,分析SCF表达与肿瘤部位、大小、病理性核分裂象/50HPF、危险度分级及Ki-67指数的关系。检测GIST标本中c-kit基因的突变状态,分析其与SCF表达的关系。结果 68例GIST组织中,SCF表达率为76%(52/68)。SCF表达阳性的GIST组织中,Ki-67增殖指数和病理性核分裂象明显增高、增多。SCF的表达与c-Kit基因的突变状态无明显相关。结论 GIST组织中存在SCF的自分泌,SCF表达可能促进肿瘤细胞增殖。     

多靶点激酶抑制药GNF-7对白血病细胞表达谱的影响

目的探索多靶点激酶抑制药GNF-7对白血病细胞表达谱的影响。方法从基因表达公共数据库下载表达谱数据集GSE49534,用BRB-Array Tools软件包筛选差异表达基因(DEGs),分别对差异基因进行基因本体(GO)功能分析、通路富集分析、基因互作网络分析和通路互作网络分析。结果共筛选出847个差异基因,其中上调表达基因426个,下调表达基因419个。DEGs发挥的分子功能集中在结合、蛋白激酶活性和信号转导因子活性等,主要参与信号转导、小分子代谢和细胞凋亡等生物学过程。DEGs显著富集的通路有核糖体合成、代谢通路、Janus激酶-信号转导和转录激活因子(JAK-STAT)信号通路等。网络分析挖掘出的核心基因有多核糖核苷酸核苷酸转移酶1(PNPT1)、腺苷酸激酶4(AK4)、Janus激酶2(JAK2)、信号转导和转录激活因子2(STAT2)、MYC,核心pathway包括丝裂原活化蛋白激酶(MAPK)信号通路、凋亡、细胞周期和肿瘤通路等。结论 GNF-7通过诱导凋亡和细胞周期阻滞等抑制白血病细胞。