急性髓系白血病靶向药物治疗新进展

急性髓系白血病(AML)是一种髓系细胞恶性克隆性疾病。近年来, 新型靶向药物的出现使癌症治疗发生了革命性变化, 有望在AML治疗上取得突破性进展。这些新药包括二代DNA甲基转移酶抑制剂、靶向B细胞淋巴瘤因子2(BCL-2)抑制剂、FMS样酪氨酸激酶3(FLT3)抑制剂、异柠檬酸脱氢酶抑制剂、抗CD33单克隆抗体、Smoothened Inhibitor(SMO)抑制剂、肿瘤蛋白p53靶向药物、抗CD47单抗、核输出蛋白1(XPO1)抑制剂等。本文就AML最新靶向治疗药物作一综述。     

成人急性髓系白血病治疗现状及新药研究进展

急性髓系白血病（Acute myeloid leukemia, AML）是一类高度异质性疾病,过去常规诱导化疗和各类支持治疗为主,但随着二代测序等技术应用以来,AML药物迅速发展。本文从细胞毒药物、小分子靶向药物以及免疫靶向药物等方面,系统概述AML的致病机制,以及临床研究中较为前沿的各类新型药物（如FLT3抑制剂Midostaurin、IDH抑制剂AG-221和CPX-351等）的研究进展,旨在为AML的新药研发提供参考。     

维奈克拉联合用药治疗急性髓系白血病的研究进展

Bcl-2是调控肿瘤细胞凋亡的关键分子,也是近年研究证实的白血病治疗新靶点。针对该靶点的Bcl-2抑制剂维奈克拉与去甲基化药物的联合用药方案于2018年11月获美国食品和药物管理局批准,用于治疗75岁及以上初治或有合并症不适合高强度化疗的急性髓系白血病(AML)患者。多项研究证实维奈克拉联合去甲基化药物或小分子抑制剂在治疗初治老年AML或复发/难治性AML患者等方面取得显著疗效。     

骨髓增生异常综合征及急性髓系白血病表观遗传学治疗进展

表观遗传学改变在骨髓增生异常综合征(MDS)及急性髓系白血病(AML)的发病机制中起重要作用,也因此成为了重要的治疗靶点.虽然现阶段大部分表观遗传学药物作用机制尚不完全明确,临床治疗中面临着应答率低、联合治疗不良反应多和易复发等问题,无法给患者带来明确的生存效益;但是对于无法耐受强化治疗的患者,表观遗传学治疗是一种可以考虑的治疗方法.本研究旨在综述现阶段可能改善MDS及AML患者预后的几种表观遗传学药物,并指出现阶段治疗的不足及未来努力的方向.     

成纤维细胞生长因子信号通路及其相关抑制剂治疗肝癌的研究进展

成纤维细胞生长因子(FGF)是肽类分子,其通过与细胞膜上特异性受体的结合来发挥作用,调节细胞增殖、分化、凋亡及代谢等过程.靶向FGF信号通路的抑制剂治疗肝癌,显示出很好的疗效.本文综述了FGF信号通路与肝癌发生的关系以及靶向FGF信号通路治疗肝癌的抑制剂的临床研究进展.     

子宫内膜癌靶向药物治疗研究进展

子宫内膜癌的化疗耐药性问题显著,迫切需要新的治疗方案。随着对肿瘤发病机制和信号传导通路的深入研究,以及表观遗传修饰作用机制的阐明,靶向药物研究为子宫内膜癌的治疗提供了新的方法和手段。本文综述了表皮生长因子受体拮抗剂、血管内皮生长因子抑制剂、PI3K/Akt/mTOR通路抑制剂、PD-1/PD-L1抑制剂和表观遗传修饰抑制剂等靶向药物在子宫内膜癌治疗领域的研究进展,为临床用药提供新思路。     

急性髓系白血病基因水平发病机制的研究进展

白血病是一种常见的血液系统恶性肿瘤,其中急性髓系白血病(acute myeloid leukemia,AML)是所有白血病中最常见的一类以克隆性髓系原始细胞增高为主的造血系统恶性疾病,其发病机制尚不完全清楚,现认为是由多种因素在多个层面、多个阶段的相互作用而导致的。随着国内外现代医学事业的不断发展和进步,对急性髓系白血病在基因水平上发病机制的深入研究,开发出的新型基因靶向治疗药物因其能特异性地作用于病变部位,而且效果显著、毒性相对低等特点,使AML的治疗方案不断得以优化,预后也有很大的改善,为临床上高效安全地治疗AML带来新希望。本文拟对AML在基因水平上发病机制的研究进展进行综述,旨在寻找潜在的基因靶点,为开发精准治疗AML的新型基因靶向药物提供参考。     

Bcl-2蛋白的小分子抑制剂

Bcl-2蛋白家族在调节细胞凋亡中发挥重要作用，人类恶性肿瘤细胞高表达Bcl-2和Bcl-XL，而高表达这些抗凋亡分子的细胞对于化疗药物有抗性，因此，以Bcl-2家族蛋白为靶点的小分子抑制剂成为很有潜力的可用于多种肿瘤治疗的药物，通过下调Bcl-2和Bcl-XL的表达直接影响肿瘤细胞的存活及其对化疗药物的抗性。     

治疗急性髓系白血病新药：Hedgehog信号通路抑制剂glasdegib

急性髓系白血病(AML)是成人常见的急性白血病。Hedgehog信号通路的异常与AML的发病密切相关。glasdegib (Gla)为一种Hedgehog信号通路抑制剂,由辉瑞制药公司生产,于2018年11月由美国食品和药物管理局批准上市,与低剂量阿糖胞苷联合用于治疗新确诊的75岁及以上或因其他合并症而无法接受高强度化疗的AML患者。临床试验表明,Gla联合低剂量阿糖胞苷可明显改善患者的生存期。最常见的不良反应包括贫血、疲劳、出血、发热、中性粒细胞下降、肌肉疼痛、血小板减少和呼吸困难等。     

分子靶向药物治疗非小细胞肺癌的临床研究进展

分子靶向药物是利用肿瘤细胞与正常细胞之间分子细胞生物学上的差异,采用封闭受体、抑制血管生成、阻断信号传导通路等方法作用于肿瘤细胞特定的靶点,特异性地抑制肿瘤细胞的生长,促使肿瘤细胞凋亡.分子靶向治疗比传统的化疗特异性强、毒副反应小,将成为今后肿瘤治疗的新趋势.综述了近年来分子靶向药物治疗非小细胞肺癌的临床研究和应用.     

Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML.

Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival. Although abnormalities of mTOR signaling are strongly associated with neoplastic leukemic proliferation, the role of pharmacologic inhibitors of mTOR in the treatment of AML has not been established.

Expert opinion: Inhibition of mTOR signaling has in general modest growth-inhibitory effects in preclinical AML models and clinical trials. Yet, combination of allosteric mTOR inhibitors with standard chemotherapy or targeted agents has a greater anti-leukemia efficacy. In turn, dual mTORC1/2 inhibitors, and dual PI3K/mTOR inhibitors show greater activity in pre-clinical AML models. Further, understanding the role of mTOR signaling in stemness of leukemias is important because AML stem cells may become chemoresistant by displaying aberrant signaling molecules, modifying epigenetic mechanisms, and altering the components of the bone marrow microenvironment.     

黄芪对老年急性髓系白血病患者BCL-2家族凋亡因子的相关影响

目的：本研究探讨黄芪（astragalus）对老年急性髓系白血病患者疗效评估,并检测其对患者Bcl-2家族凋亡相关因子的影响,从而探讨黄芪对老年急性髓系白血病患者治疗的作用机制。方法随机分配42例老年急性髓系白血病患者,分为对照组和治疗组,两组均予以化疗,治疗组在此基础上给予黄芪,统计两组病患治疗后完全缓解率,患者治疗后白血病细胞凋亡情况运用流式细胞仪检验,患者治疗前后Bcl-2,Bax、Bak、BCL-xl的mRNA表达状况运用RT-PCR方法进行检测,统计两组患者治疗后疗效情况。结果治疗组患者明显优于对照组,治疗组患者完全缓解率高于对照组（P<0.05）。治疗组患者给予黄芪后,白血病细胞凋亡较对照组明显增高,治疗组治疗后Bcl-2、Bcl-xl、Bax、Bak的表达较治疗前差异有统计学意义（P<0.05）,其中Bcl-2、Bcl-xl较治疗前明显下降,Bax、Bak较治疗前明显升高;对照组治疗后Bcl-2、Bax、Bak、BCL-xl表达水平较对治疗前差异无明显统计学意义（P>0.05）。结论黄芪能促进白血病细胞的凋亡,提高患者疗效,其机制可能是通过减低Bcl-2、BCL-xl的表达,增加Bax、Bak的表达来完成。     

Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia

Background: The PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation and survival not only under physiological conditions but also in a variety of tumor cells. Therefore, the PI3K/Akt/mTOR axis may be a critical target for cancer therapy. Objective: This review discusses how PI3K/Akt/mTOR signaling network is constitutively active in acute myelogenous leukemia (AML), where it strongly influences proliferation, survival and drug-resistance of leukemic cells, and how effective targeting of this pathway with pharmacological inhibitors, used alone or in combination with existing drugs, may result in suppression of leukemic cell growth, including leukemic stem cells. Methods: We searched the literature for articles dealing with activation of this pathway in AML and highlighting the efficacy of small molecules directed against the PI3K/Akt/mTOR signaling cascade. Conclusions: The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.     

急性髓系白血病blc—2与bax基因的比值和耐药

目的：了解凋亡抑制基因（Bcl-2)、凋亡诱导基因（Bax)在急性髓系白血病的表达及Bcl-2/Bax比值与耐药关系。方法：用免疫组织化学法检测Bcl-2、Bax抗原表达,细胞培养四氮唑蓝比色法（MTT）药敏试验检测急性髓系白血病（AML）耐药的情况。结果：AML患者Bcl-2高于正常对照组,Ｂax低于正常对照级,其Bcl-2/Bax比值显著高于正常对照组（P＜0．01）。产生耐药组的病例Bcl-2/Bax高于敏感组（P＜0．05）,Bcl-2/Bax高比值患者化疗反应差（P＜0．05）。结论：Bcl-2,Bax的异常表达在AML形成、发展和产生耐药起一定作用,检测Bcl-2,Bax比值对治疗药物选择、预后的判断有重要意义。     

组蛋白去乙酰化酶抑制剂联合FMS样酪氨酸激酶-3抑制剂对FLT3-ITD突变白血病细胞增殖、凋亡和周期的影响

目的 探讨组蛋白去乙酰化酶抑制剂(HDACi)联合FMS样酪氨酸激酶-3(FLT3)抑制剂对FLT3-ITD突变的急性髓系白血病(AML)细胞系增殖抑制作用及其相关机制。方法 将西达本胺(Chidamide)和奎扎替尼(Quizartinib, AC220)以不同浓度单药或联合作用于MV4-11、MOLM-13细胞系48 h后,CCK8检测细胞增殖能力;Compusyn 1.0软件分析两药联合作用的协同效应;流式细胞计数法测定各组细胞凋亡率、增殖周期;蛋白质印迹法测定P53、Bcl-2、Bax、FLT3、磷酸化FLT3(p-FLT3)及磷酸化AKT(p-AKT)蛋白表达水平。结果 随西达本胺及奎扎替尼单药或联合作用浓度升高,对MV4-11及MOLM-13细胞系的48h增殖抑制率均显著升高(P<0.05),并且两药具有协同抑制效应(均CI值<1)。在奎扎替尼1.0 nmol/L+西达本胺1.0μmol/L作用48 h后,细胞凋亡率MV4-11细胞株为31.697%±5.648%,MOLM-13细胞株为18.500%±1.751%,细胞周期阻滞于G0/G1期的比例MV4-11细...     

Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies.In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.     

Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia

Apoptosis plays a key role in the control of rapidly renewing tissues, such as the hematopoietic system and leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells and the development of drug resistance. These defects are also frequently associated with a low rate of response to standard chemotherapy and with a poor survival in acute myeloid leukemia (AML). The major form of apoptosis proceeds through the mitochondrial pathway, with the mitochondrial outer membrane permeabilization, leading to the release of proteins normally found in the space between the inner and outer mitochondrial membranes (cytochrome C, AIF and others). Higher levels of anti-apoptosis proteins bcl-2, bcl-x(L), Mcl-1 block permeabilization of the membrane and are reported in AML patients presenting a poor outcome. On the contrary, activated pro-apoptotic bax or bad proteins allow this permeabilization and are correlated to a good prognosis in AML. Defects in the mitochondrial pathway induce multidrug-resistance and confer important prognostic information in AML. High ratios of bcl-2 to bax protein confer a poor prognosis with decreased rates of complete remission and overall survival. The prognostic information from the ratio of the proteins is greater than bcl-2 levels alone. Recently, we confirmed the impressive impact of the bax/bcl-2 ratio, determined by flow cytometry, on AML prognosis (complete remission and overall survival) in 255 AML patients. Bcl-2 down regulation might lower the apoptotic threshold of leukemic cells and, through this mechanism, favor response to chemotherapy. Phase II studies of oblimersen (antisense Bcl-2), cytarabine and daunorubicin or oblimersen plus gentuzumab, a cytotoxic antibody directed against CD33+ cells in relapsed AMLs, showed promising results. Defects in apoptosome proteins, such as APAF-1, are frequent in AML and treatment with 5-aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, restored APAF-1 expression in leukemic cells. In conclusion, targeted therapies that are designed to induce apoptosis in leukemic cells, are the most promising anti-leukemia strategies. The elucidation of the apoptotic machinery and of its defects in AML lays the basis for developing new drugs able to trigger apoptosis and overcome therapy resistance.     

Bcl-2反义核酸联合化疗药对HL60细胞及原代白血病细胞的作用

目的应用Bcl-2反义硫代磷酸寡脱氧核苷酸(anti-sense phosphorothioate oligodeoxynucleotide,AS-PS-ODNs,AS-PO)靶向诱导20例原代急性白血病细胞凋亡,并与多种常用化疗药联合,观察ASPO对原代急性白血病细胞及HL60细胞系的协同效应。方法①应用MTT比色法分析ASPO与常用化疗药物配伍协同作用特点;②细胞免疫化学染色检测P26 Bcl-2蛋白表达;③台盼蓝拒染试验检测白血病细胞倍增时间;④丫啶橙(AO)染色,流式DNA Content分析细胞凋亡率,电镜及DNA电泳观察凋亡细胞形态及分子水平的变化。结果①ASPO与除DNR,NVT外的7种(HHRT,VCR、MTX、Ara-c、VP16、ACR、DEX)化疗药物均有联合增强或相加作用。②12例Bcl-2蛋白抑制率大于0.4为A组,8例小于0.4为B组。A组的凋亡率和B组的凋亡率均高于空白对照组(P<0.05),且A组的凋亡率高于B组(P<0.05)。③原代急性白血病细胞ASPO组,Ara-c组和ASPO+Ara-c组,72 h细胞生长抑制检测发现ASPO+Ara-c组的细胞抑制率高于单用ASPO与单用Ara-c的细胞抑制率之和(P<0.01);④A组的ASPO对细胞的抑制与细胞生长的倍增时间102.89±37.97呈正相关γ=0.577(P<0.05)。结论Bcl-2 ASPO能特异抑制白血病细胞(系)的Bcl-2蛋白表达;Bcl-2 ASPO对倍增时间慢、BCL-2蛋白表达高的原代白血病细胞作用效果好;Bcl-2的ASPO与多种化疗药物联合有潜在临床应用前景。     

Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug

Currently, Arsenic Trioxide (ATO) is considered the treatment of choice for patients with relapsed acute promyelocytic leukemia (APL). Recently, a durable remission with minimal toxicity by single agent ATO or ATO + ATRA in newly diagnosed APL was reported by different groups. These regimens have minimal toxicity and can be administered on an outpatient basis after remission induction, thus they could become a real, less toxic and more economic option to ATRA + anthracyclines in particular in low risk APL, or in patients that cannot undergo chemotherapy because of age or comorbid conditions and in patients that refuse chemotherapy. Significantly, these therapies are a successful attempt to cure a tumoral disease without chemotherapy. The results of clinical trials of ATO administration as single agent in multiple myeloma (MM) and myelodisplastic syndromes (MDS) were encouraging and showed clinical effects but they were not close to APL success. On the contrary, results of clinical trials to treat non-APL acute myeloid leukemia (AML) were disappointing. We suggest that a combination therapy with drugs targeting specific pro-survival molecules or capable to enhance pro-apoptotic pathways may lead to an improvement of ATO efficacy against hematological malignancies, in particular AML. Our pre-clinical studies showed that ATO is capable to induce cell death in acute leukemia cells but the apoptotic function is limited since it can induce also a mechanism of cell defense by activating pro-survival molecules such as MEK-ERK, Bcl-xL, Bcl-2. By combining ATO with specific MEK inhibitors, we demonstrated that the block of MEK-ERK phosphorylation, the induction of Bad de-phosphorylation, and activation of p53AIP1 apoptotic pathway interrupt the pro-survival mechanisms of ATO and kill the leukemic cells by apoptotic synergism. Our results provide an experimental basis for combined or sequential treatment with MEK inhibitors and ATO in AML. The renaissance of ATO as a drug in moderne medicine may be considered, together with ATRA success, a victory of empirical analysis, that had (and has) great impact on Chinese culture.