复发性滤泡性淋巴瘤治疗新药copanlisib的药理作用与临床评价

滤泡性淋巴瘤发病率居非霍奇金淋巴瘤第2位,因其缓解后易复发,给临床治疗带来极大困难。2017年9月,FDA加速批准磷脂酰肌醇3-激酶抑制剂(PI3K抑制剂)copanlisib上市,用于至少接受过两次全身治疗的成人复发性滤泡性淋巴瘤。临床研究显示,copanlisib有较好的客观缓解率。本文就其药理作用、临床评价、安全性及用法用量等做一综述。     

Idelalisib的严重不良反应及临床处理概述

摘要：Idelalisib是用于治疗恶性血液病的选择性磷脂酰肌醇-3-激酶$亚型抑制药。尽管它在临床上有显著疗效,但是严重药品不良反应必须高度关注。本文描述了该药相关的肝毒性、腹泻或肠炎、肺炎和感染等严重不良反应,提供了临床诊断和处理的指南。     

医药快讯

美国FDA批准抗肿瘤药Idelalisib上市美国 FDA 于2014年7月23日批准吉利德（ Gilead ）公司的Idelalisib （商品名：Zydelig ）片剂上市,用于治疗复发性慢性淋巴细胞白血病（ CLL ）、复发性滤泡性 B 细胞非霍奇金淋巴瘤、复发性小淋巴细胞淋巴瘤（ SLL ）。Idelalisib为磷脂酰肌醇3-激酶（PDK）8抑制药,P13K8可在正常和恶性B细胞中表达。Idelalisib可诱导恶性B细胞和原发肿瘤细胞的细胞系凋亡并抑制其增殖。Idelalisib也可抑制多种细胞信号通路,包括B细胞受体信号、趋化因子受体（CXCR）4和CXCR5信号。Idelalisib用于治疗淋巴瘤细胞还可抑制细胞趋药性和黏附力并降低细胞活性。     

Idelalisib

<正>Idelalisib由美国吉利德科学公司(Gilead Sciences,Inc.)研发,于2014年7月23日获美国食品药品监督管理局(FDA)批准上市,商品名为Zydelig。该药是FDA批准的首个选择性阻断磷脂酰肌醇-3激酶(PI3K-delta)的抗癌药物,主要用于复发性慢性淋巴细胞白血病(CLL)、滤泡B细胞非霍奇金淋巴瘤(FL)和小细胞淋巴瘤(SLL)     

新型磷脂酰肌醇-3激酶δ抑制剂idelalisib

磷脂酰肌醇-3激酶(PI3K)是一种胞内磷脂酰肌醇激酶,吉利德正在开发的血癌新药idelalisib是首个选择性口服PI3K抑制剂,与α、β、γ亚基相比,其可高度选择性地作用于δ亚基。idelalisib可阻滞PI3Kδ-Akt信号通路并促进细胞凋亡,从而有效治疗难治性惰性非霍奇金淋巴瘤(iNHL)。研究表明idelalisib能够显著增加B细胞急性淋巴细胞白血病(B-ALL)和慢性淋巴细胞白血病(CLL)细胞系的凋亡,同时没有显著增加正常T细胞的凋亡。在一系列临床研究中显示出良好的治疗前景,且安全性及耐受性均较好。     

PI3K/Akt/mTOR通路在炎症相关疾病中分子机制研究进展

炎症是一种机体应对感染、组织损伤或者细胞应激的反应,并且可以通过修复机制恢复组织功能。炎症发生时会引起多条信号通路的激活,包括核转录因子-κB（NF-κB）通路、Janus激酶/信号转导与转录激活子（JAK/STAT）通路、丝裂原活化蛋白激酶（MAPK）通路以及磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白（PI3K/Akt/mTOR）通路等。本文综述了近年来磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白通路在炎症相关疾病中的分子作用机制,为研发以磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白为靶点的药物提供理论依据。     

用于肿瘤治疗的PI3K/mTOR双重抑制剂的研究进展

磷脂酰肌醇3-激酶（PBK）是细胞内重要的信号转导分子,在细胞存活、增殖和分化过程中起重要调节作用。且是磷脂酰肌醇3-激酶／蛋白激酶B／雷帕霉素靶蛋白信号转导通路的关键节点蛋白,与细胞周期、血管形成、肿瘤发生和侵袭的关系密切,现已证实PBKs是潜力巨大的药物治疗靶点,针对该通路的抑制剂近年来成为研究热点,抗肿瘤治疗前景看好。     

治疗复发性滤泡性淋巴瘤新药:可泮利塞

可泮利塞为一种Ⅰ型磷脂酰肌醇3-激酶抑制剂,由拜耳制药公司研发,于2017年9月获美国食品和药物管理局加速批准,用于治疗前期至少接受过两次系统治疗的复发性滤泡性淋巴瘤。推荐给药方法为疗程的第1、 8和15日给予可泮利塞60 mg, 1 h内静脉输注, 28 d为一个疗程。可泮利塞最常见不良反应包括血糖升高、腹泻、高血压、白细胞减少、下呼吸道感染及血小板减少等。     

弥漫性大B细胞淋巴瘤常见致病信号通路及其靶向药物的研究进展

弥漫性大B细胞淋巴瘤是亚洲人最常见的淋巴肿瘤亚型,经过R-CHOP方案治疗后仍有相当一部分患者表现为难治或复发。弥漫性大B细胞淋巴瘤的常见致病信号通路有B细胞受体、Toll样受体4/髓样分子因子88/核因子-κB、磷脂酰肌醇3-激酶/蛋白激酶B信号通路,靶向药物包括Bruton酪氨酸激酶抑制剂、来那度胺、硼替佐米、凋亡蛋白抑制剂抑制剂、磷脂酰肌醇3-激酶抑制剂、蛋白激酶B抑制剂、哺乳动物雷帕霉素靶蛋白抑制剂。阐述了弥漫性大B细胞淋巴瘤中常见致病信号通路及其遗传学改变,并总结了相关通路常见的靶向药物的研究进展。     

选择性PI3K抑制剂的研究进展

磷脂酰肌醇3-激酶（PI3K）是细胞内重要的信号转导分子,在细胞存活、增殖和分化过程中起重要调节作用。PI3K是PI3K/AKT/mT0R信号转导通路中的关键节点蛋白,调控着重要的生命活动。现已证实磷脂酰肌醇3-激酶（PI3Ks）是潜力巨大的药物治疗靶点,特别是PI3Kα现己成为抗肿瘤治疗的重要靶点之一。目前己有多种针对PI3Ks的抑制剂进入临床研究。然而现有抑制剂的化学类型不多且选择性不高、临床应用受局限。因此积极研究和开发结构新颖的PI3K选择性抑制剂对于疾病的靶向治疗具有重要意义。本文将对选择性PI3K抑制剂在抗肿瘤方面的研究进展作一综述。     

PI3K isoform-selective inhibitors: next-generation targeted cancer therapies

The pivotal roles of phosphatidylinositol 3-kinases (PI3Ks) in human cancers have inspired active development of small molecules to inhibit these lipid kinases. However, the first-generation pan-PI3K and dual-PI3K/mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent as well as a relatively high rate of side effects. It is increasingly recognized that different PI3K isoforms play non-redundant roles in particular tumor types, which has prompted the development of isoform-selective inhibitors for pre-selected patients with the aim for improving efficacy while decreasing undesirable side effects. The success of PI3K isoform-selective inhibitors is represented by CAL101 (Idelalisib), a first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of chronic lymphocytic leukemia, indolent B-cell non-Hodgkin''s lymphoma and relapsed small lymphocytic lymphoma. Inhibitors targeting other PI3K isoforms are also being extensively developed. This review focuses on the recent progress in development of PI3K isoform-selective inhibitors for cancer therapy. A deeper understanding of the action modes of novel PI3K isoform-selective inhibitors will provide valuable information to further validate the concept of targeting specific PI3K isoforms, while the identification of biomarkers to stratify patients who are likely to benefit from the therapy will be essential for the success of these agents.     

磷脂酰肌醇3-激酶抑制剂抗肿瘤临床研究进展

对磷脂酰肌醇3-激酶（Phosphatidyl inositol 3-kinase,PI3K）抑制剂作为抗肿瘤药物的临床研究进展作一综述。PI3K在细胞生长,增殖和凋亡等过程中起重要调节作用,与乳腺癌、卵巢癌、前列腺癌等肿瘤的发生发展密切相关。因此,PI3K已成为很有前途的癌症治疗靶标,超过10多种PI3K抑制剂作为抗肿瘤药物已进入临床研究。     

The serine-threonine kinase p90RSK is a new target of enzastaurin in follicular lymphoma cells

BACKGROUND AND PURPOSE

Follicular lymphoma is the second most common non-Hodgkin''s lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems.

EXPERIMENTAL APPROACH

The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment.

KEY RESULTS

Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3β. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice.

CONCLUSIONS AND IMPLICATIONS

The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.     

Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3K inhibitor for cancer therapy. Dozens of other PI3K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers, etc. This review provides an introduction to PI3K and summarizes key advances in the development of PI3K inhibitors.     

Approved and emerging PI3K inhibitors for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma

ABSTRACT

Introduction

PI3K inhibition with idelalisib (at that time CAL-101) was at the forefront of the development of molecularly targeted therapies in Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) and follicular lymphoma. However, after initial approval, subsequent trials identified specific immune-mediated and infectious toxicity that led to a reduced use and stopped the further development of this agent. PI3K inhibition as a treatment paradigm fell out of favor compared to other developments such as BTK or BCL2 inhibitors.     

Present and future of PI3K pathway inhibition in cancer: perspectives and limitations

Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival, motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over-expression of PI3Ks and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I PI3Ks (α, β, γ, δ isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein, we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on potential side effects, caveats and limitations for PI3K blockade in patients.     

Identification of NVP-BKM120 as a Potent,Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer

相似文献   

Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies

Introduction: The B-cell receptor (BCR) is critical for the development and persistence of B-cell non-Hodgkin lymphoma (B-NHL). Protein kinase C-beta (PKC-β) has been identified as one of the key signaling hubs downstream of the BCR and constitutes a valuable target in B-NHL. As a potent PKC-β inhibitor, enzastaurin is currently being tested in Phase II/III trials.

Areas covered: This review summarizes the latest results and ongoing clinical trials with enzastaurin in light of basic scientific advances in the understanding of various lymphoid cancers, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM).

Expert opinion: While its continued clinical development is uncertain, enzastaurin should be regarded as a stepping stone for the development of future therapies; indeed, the recent research has provided valuable insight into the possible molecular mechanisms that explain its limited clinical activity especially in the treatment of DLBCL and MCL. It should be noted that there is still some interest in enzastaurin, in combination, for the treatment of WM.     

Phosphatidylinositol 3-kinase isoforms as novel drug targets

Phosphatidylinositol 3-kinases (PI3Ks) are key molecules in the signal transduction pathways initiated by the binding of extracellular signals to their cell surface receptors. The PI3K family of enzymes comprises eight catalytic isoforms subdivided into three classes and control a variety of cellular processes including proliferation, growth, apoptosis, migration and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer, but is also involved in other commonly occurring diseases such as chronic inflammation, autoimmunity, allergy, atherosclerosis, cardiovascular and metabolic diseases. The fact that the PI3K pathway is deregulated in a large number of human diseases, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. However, due to the complexity of PI3K signaling pathways, developing an effective anti-cancer therapy may be difficult. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments. In this article we will give an overview of the complex role of PI3K isoforms in human diseases and discuss their potential as drug targets. In addition, we will describe the drugs currently used in clinical trials, as well as promising emerging candidates.