脾酪氨酸激酶抑制剂治疗慢性淋巴细胞白血病的机制与现状

慢性淋巴细胞白血病(CLL)是一种以单克隆B淋巴细胞增殖为特征,尚不能彻底治愈的血液系统肿瘤。一些新型小分子药物的出现为复发/难治的CLL患者提供了新的治疗策略,包括布鲁顿酪氨酸激酶(BTK)抑制剂、磷脂酰肌醇3 激酶(phosphoinositide 3 kinase delta, PI3K)抑制剂、脾酪氨酸激酶(Syk）抑制剂等。本文就Syk抑制剂在CLL中的作用机制及近年来的研究进展进行综述。     

慢性淋巴细胞白血病/小淋巴细胞淋巴瘤靶向治疗的最新研究进展

慢性淋巴细胞白血病（CLL）/小淋巴细胞淋巴瘤（SLL）是一种相对惰性的B淋巴细胞增殖性疾病。近年来,随着新药的上市,化疗逐渐被靶向治疗所取代,明显延长了患者生存期并减低了治疗副作用。目前研究较多的CLL/SLL靶向治疗药物有BTK抑制剂、PI3K抑制剂、SYK抑制剂和BCL-2抑制剂。本文就不同种类靶向治疗药物在CLL/SLL治疗中的最新研究进展作一综述。     

BTK抑制剂联合苯达莫司汀、利妥昔单抗一线治疗慢性淋巴细胞白血病/小淋巴细胞淋巴瘤的疗效及安全性北大核心CSCD

慢性淋巴细胞白血病(CLL)/小淋巴细胞淋巴瘤(SLL)在西方发病率高,是成人最常见的白血病,我国的发病率低于西方,但呈不断增长趋势。小分子靶向药物布鲁顿酪氨酸激酶(BTK)抑制剂(BTKi)、促凋亡蛋白Bcl-2抑制剂(BCL-2i)维奈克拉(Ven)等治疗CLL/SLL具有疗效好、不良反应小、口服方便等特点[1-4],显著优于传统化学免疫治疗,CLL治疗逐渐进入以BTKi为代表的无化疗时代[3]。我国已批准第一代BTKi伊布替尼及国产第二代BTKi泽布替尼、奥布替尼治疗CLL。     

Zanubrutinib在B细胞淋巴瘤中的临床应用

Zanubrutinib是我国自主研发的一种具有高选择性的二代布鲁顿酪氨酸激酶(BTK)抑制剂,也是首次获得美国食品及药物管理局(FDA)批准的新型抗肿瘤药物。近年来,随着分子靶向药物诞生,部分B细胞淋巴瘤的治疗逐渐进入了无化疗的靶向时代,免疫治疗也逐渐被应用于临床,特别是在一些复发难治的淋巴瘤中,都显示出了深度持久的缓解及良好的安全性,为精准治疗奠定了基础。本文主要是针对zanubrutinib在B细胞淋巴瘤中的临床应用及最新研究进展作一综述。     

晚期非小细胞肺癌表皮生长因子受体酪氨酸激酶小分子抑制剂靶向治疗现状和展望

近年来,分子靶向治疗已成为晚期非小细胞肺癌(NSCLC)治疗可供选择策略之一。表皮生长因子受体(EGFR)通路作为促进肿瘤细胞增殖和侵袭的关键信号转导通路日益受到人们关注。针对该信号通路进行干预成为一个有前途的肺癌治疗策略。其中,特别是EGFR酪氨酸激酶小分子抑制剂(EGFR-TKI)已成为肺癌治疗领域研究的热点。EGFR-TKIs是一类能作用于细胞内EGFR酪氨酸激酶区的小分子药物,能抑制酪氨酸激酶磷酸化和下游信号传导,从而发挥抗肿瘤效应。     

泽布替尼治疗慢性淋巴细胞白血病/小淋巴细胞淋巴瘤的研究现状

慢性淋巴细胞白血病(CLL)/小淋巴细胞淋巴瘤(SLL)以成熟B淋巴细胞的克隆扩增为主要特征, 好发于中老年人群, 临床进展缓慢, 但难以治愈, 并且不同患者的预后具有高度异质性。泽布替尼为口服新型共价Bruton酪氨酸激酶(BTK)抑制剂, 其可与BTK活性位点中的半胱氨酸形成共价键, 从而抑制BTK活性, 以发挥抗肿瘤作用。笔者通过共价BTK抑制剂的概述、泽布替尼单药和联合治疗CLL/SLL、泽布替尼和伊布替尼的对比研究方面, 对泽布替尼应用于CLL/SLL的研究现状进行阐述。     

耐甲磺酸伊马替尼慢性髓系白血病治疗策略研究进展

抑制BCR—ABL酪氨酸激酶作为慢性髓系白血病的靶向治疗,已经取得了显著的临床疗效。但对现有药物甲磺酸伊马替尼逐渐显现的原发及继发耐药,为CML治疗带来了新的挑战。针对BCR—ABL酪氨酸激酶及耐伊马替尼机制寻找新的更为有效的治疗靶点是目前探索的热点。本文对目前伊马替尼失效的机制和影响BCR—ABL酪氨酸激酶途径新靶点的研究作一综述。     

蛋白酪氨酸激酶在骨肉瘤治疗中的研究进展

骨肉瘤是一种常见的恶性骨肿瘤,其治疗方法目前有化疗、外科手术以及靶向治疗等.蛋白酪氨酸激酶(PTK)是一类具有酪氨酸激酶活性的蛋白质,在细胞生长、增殖、分化中具有重要作用,以蛋白酪氨酸激酶为靶点进行靶向治疗成为目前国际上抗肿瘤药物研究的热点.文章就蛋白酪氨酸激酶在骨肉瘤中作用的研究进展进行综述.     

靶向PI3K信号通路抑制剂在胰腺癌治疗中的研究进展

胰腺癌（Pancreatic Cancer,PC）作为高侵袭性恶性肿瘤，其发病率逐年上升。对于不适合手术治疗的患者，靶向治疗具有明显优势。肿瘤细胞的增殖、凋亡及血管生成等生物学行为受磷脂酰肌醇3激酶信号通路的调节，使用PI3K抑制剂可改善患者预后。目前靶向PI3K抑制剂，已在淋巴造血系统肿瘤和其它实体瘤的临床试验中取得较好结果，但在胰腺癌中研究较少。基于此，我们回顾了PI3K通路研究情况，并就靶向PI3K信号通路抑制剂在胰腺癌治疗中的新进展作一综述。     

Ibrutinib 治疗慢性淋巴细胞白血病及其他 B 细胞恶性肿瘤简

慢性淋巴细胞白血病和非霍奇金淋巴瘤等成熟B细胞肿瘤患者的存活和疾病进展依赖B细胞受体（BCR）提供的信号,而Bruton酪氨酸激酶（BTK）是BCR信号通路上的关键激酶.Ibrutinib是一种新型的BTK选择性抑制剂,对BTK具有不可逆的抑制作用,在B细胞肿瘤的初步临床试验显示了令人振奋的疗效.本文就其作用机制以及在B细胞肿瘤的研究现状进行综述.     

BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia

Patients with BRAFV^600E/K-driven melanoma respond to the BRAF inhibitor vemurafenib due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In BRAF WT cells and those with mutations that activate or result in high levels of the BRAF activator RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We describe a patient with malignant melanoma who developed chronic lymphocytic leukemia (CLL) in the absence of RAS mutations during vemurafenib treatment. BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK/ERK in primary CLL cells from additional patients. BRAF inhibitor–driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect. Additionally, the RAS-GTP/RAS ratio in primary CLL cells exposed to vemurafenib was reduced upon SYK inhibition. BRAF inhibition increased mortality and CLL expansion in mice harboring CLL xenografts; however, SYK or MEK inhibition prevented CLL proliferation and increased animal survival. Together, these results suggest that BRAF inhibitors promote B cell malignancies in the absence of obvious mutations in RAS or other receptor tyrosine kinases and provide a rationale for combined BRAF/MEK or BRAF/SYK inhibition.     

原发性中枢神经系统淋巴瘤的治疗新进展

原发性中枢神经系统淋巴瘤(PCNSL)是一种罕见的侵袭性淋巴结外非霍奇金淋巴瘤,目前基于甲氨蝶呤的大剂量化疗是新诊断的PCNSL的标准诱导治疗方案,但复发/难治性和老年PCNSL的有效治疗仍不明确,随着临床试验的进行,不断出现新的药物和联合治疗方法,如利妥昔单抗和依鲁替尼的加入增加了难治复发患者的缓解率,而来那度胺对老年患者的维持治疗显示出良好的活性,本文将对免疫检查点抑制剂、免疫调节药物、布鲁顿酪氨酸激酶和PI3K/AKT/mTOR通路抑制剂等最新研究进展作一综述。     

Targeted Therapy in Chronic Lymphocytic Leukemia: Past,Present, and Future

Background

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world. Recent advances in understanding the biology of B-cell malignancies have resulted in the development of novel agents targeting key prosurvival pathways in the neoplastic B cell.

Objective

The goal of this article was to summarize current literature on the emerging therapeutic approaches in CLL and B-cell malignancies.

Methods

A literature review was performed, identifying pathways and key clinical trials involving novel therapies in CLL, with special emphasis on B-cell receptor (BCR)-targeting agents.

Results

Understanding the biology of the BCR-signaling pathway has led to identification of novel molecular targets. Most notably, inhibitors of Bruton tyrosine kinase and phosphatidylinositide 3-kinase-δ have entered clinical trials and demonstrated high response rates in CLL, including high-risk disease. Cyclin-dependent kinase inhibitors may evolve into an alternative therapeutic approach in CLL. New drugs that target molecules within and outside of the BCR-signaling pathway have shown promise in preclinical studies.

Conclusions

Both preclinical and early clinical trial results involving novel targeted therapies suggest that the standard treatment paradigm in CLL and B-cell malignancies will soon change. Particular attention should be paid to the BCR-targeting agents, whose favorable adverse effect profile may improve the lives of elderly patients with CLL.     

Bruton's tyrosine kinase is essential for human B cell tolerance

Most polyreactive and antinuclear antibodies are removed from the human antibody repertoire during B cell development. To elucidate how B cell receptor (BCR) signaling may regulate human B cell tolerance, we tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients suffering from X-linked agammaglobulinemia (XLA). These patients carry mutations in the Bruton's tyrosine kinase (BTK) gene that encode an essential BCR signaling component. We find that in the absence of Btk, peripheral B cells show a distinct antibody repertoire consistent with extensive secondary V(D)J recombination. Nevertheless, XLA B cells are enriched in autoreactive clones. Our results demonstrate that Btk is essential in regulating thresholds for human B cell tolerance.     

磷酰肌醇-3激酶途径在CML细胞增殖和抗凋亡中的作用

为探讨磷酰肌醇-3激酶(PI3K)通路在CML细胞增殖和抗凋亡中的作用,作者应用沃氏篮酶素(Wortmannin,WT)特异性地抑制PI3K激酶活性,经细胞生长曲线测定、半固体集落培养和流式细胞膜联蛋白 V(Annexin V)标记技术,观察了K562和NB4细胞增殖能力与凋亡抗性的改变。结果:WT显著抑制K562细胞增殖能力,24,48及72小时增殖抑制率分别为23.13％。45.17％和60.42％,集落形成抑制率为53.91％(均P<0.05),而对NB4细胞的增生无明显影响;WT可促进由Vp16诱导的K562细胞凋亡。凋亡指数提高1.49倍,NB4细胞的凋亡指数无显著改变。上述结果证明了PI3K在CML细胞增殖和抗凋亡中占重要地位。     

Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date

Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor(BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.     

As2O3诱导K562细胞凋亡过程中酪氨酸蛋白激酶活性的变化

目的：阐明Ａｓ２Ｏ３诱导Ｋ５６２细胞凋亡的可能机制，为Ａｓ２Ｏ３治疗白血病的推广应用提供一定的理论基础。方法：采用免疫沉淀、Ｗｅｓｔｅｒｎｂｌｏｔ及生物化学等方法，观察在Ａｓ２Ｏ３诱导Ｋ５６２细胞凋亡过程中，细胞胞浆和胞膜蛋白及ＡＢＬ蛋白酪氨酸激酶（ＰＴＫ）活性及某些内源性蛋白酪氨酸磷酸化的变化。结果：在Ａｓ２Ｏ３诱导Ｋ５６２细胞凋亡过程中，细胞胞浆和胞膜蛋白及ＡＢＬ蛋白ＰＴＫ活性降低，分子量为１８万和１２．５万的蛋白酪氨酸磷酸化减少。结论：Ａｓ２Ｏ３可能通过降低细胞内某些蛋白，尤其ＢＣＲ／ＡＢＬ蛋白的ＰＴＫ活性，减少蛋白酪氨酸磷酸化，从而阻断ＢＣＲ／ＡＢＬ抗凋亡信号的传导，诱导Ｋ５６２细胞凋亡     

Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond

Chronic lymphocytic leukemia (CLL) remains the most incurable leukemia. Early chemotherapeutic treatments, including alkylating agents, purine nucleoside derivatives, and immunotherapeutic antibodies, only show limited benefits for patients but severe off‐target related side effects. Recent advances in understanding of the critical molecular pathways of regulating proliferation and survival of B‐CLL cells have spurred a new therapeutical strategy by selectively targeting phosphoinositide 3‐kinase delta (PI3Kδ). Idelalisib, a first‐in‐class PI3Kδ‐selective small molecule has received the FDA's fast‐track approval in July of 2014 as a new treatment of CLL, indolent B‐cell non‐Hodgkin's lymphoma, and relapsed small lymphocytic lymphoma. Undoubtedly, the success of idelalisib has provided a solid support in the development of PI3Kδ‐specific inhibitors and reformed the concept of treating CLL. However, the number of reported selective inhibitors of PI3Kδ is very limited and very few have advanced into clinical trials. The mechanism of their actions remains elusive. More profound understanding on the modes of action of new PI3Kδ inhibitors will further validate the PI3Kδ‐targeting strategy, and help to identify biomarkers capable of stratifying patients who will most likely benefit from the therapy.     

Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells

Stromal-derived factor (SDF)-1 and its G protein-coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein-coupled receptor signaling and function of mammalian precursors.     

2,4,6-Trihydroxy-alpha-p-methoxyphenylacetophenone (Compound D-58) is a potent inhibitor of allergic reactions.

The authors investigated the effects of 2,4,6-trihydroxy-alpha-p-methoxyphenylacetophenone (compound D-58), a potent inhibitor of protein tyrosine kinases SYK and Bruton's tyrosine kinase (BTK), on IgE receptor/FcepsilonRI-triggered mast cell-mediated acute allergic responses in vitro and in vivo. Compound D-58 abrogated IgE receptor/FcepsilonRI-mediated SYK and BTK activation as well as calcium mobilization in mast cells. Mast-cell degranulation and leukotriene (LT) C(4) release was inhibited by compound D-58 in a concentration-dependent fashion. Notably, compound D-58 prevented the mast cell mediator-induced vascular hyperpermeability in an in vivo murine model of passive cutaneous anaphylaxis as measured by the prevention of extravasation of systemically administered Evans blue dye. The results uniquely indicate that compound D-58 has potent antiallergic properties. Therefore, further development of compound D-58 may provide the basis for new and effective treatment programs for severe allergic disorders.