A Phase I, Open-label, Multicentre, Dose Escalation Study to Assess the Safety and Tolerability, and Pharmacokinetics of AZD1480 in Asian Patients With Advanced Solid Malignancies and Asian Patients With Child-Pugh A to B7 Advanced Hepatocellular Carcinoma (HCC) in the Escalation Phase, Estimated Glomerular Filtration Rate(EGFR) or ROS Mutant NSCLC and Non-smokers With Lung Metastasis and Gastric Cancer and Solid Tumour With Biopsy Available in the Expansion Phase.

This is Phase I, open-label and dose escalation study to evaluate the safety and tolerability of AZD1480(JAK2 inhibitor) in Asian patients with advanced solid tumors (Part A and C) and in patients with advanced HCC (Part B) in the escalation phase, EGFR or ROS mutant NSCLC and non-smokers with lung metastasis and gastric cancer in the expansion phase and to evaluate daily and BID dosing.

开始日期2010-11-01

申办/合作机构

AstraZeneca PLC

NCT01112397 / Terminated临床1期

A Phase I, Open-Label, Multi-Center, Dose-Escalation Study to Assess the Safety and Tolerability, and Pharmacokinetics of AZD1480 Administered as Daily Oral Monotherapy in Patients With Advanced Solid Malignancies in the Escalation Phase and EGFR or ROS Mutant NSCLC or Non-Smokers With Lung Metastasis in the Expansion Phase.

This study is being conducted to assess the safety, tolerability and PK of AZD1480 in patients with advanced solid malignancies.

开始日期2010-04-01

申办/合作机构

AstraZeneca PLC

NCT00910728 / Completed临床1期

A PhaseI/II, Open Label Multi-Centre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the JAK2 Inhibitor AZD1480 Administered Orally to Patients With Primary Myelofibrosis (PMF) and Post-Polycythaemia Vera/Essential Thrombocythaemia Myelofibrosis (Post-PV/ET MF

This study is being conducted to test study drug AZD1480 to see how it may work to treat myeloproliferative diseases. The main purpose of this study is to determine the safety and tolerability of AZD1480. This is the first time the drug has been given to humans and is classed as a first time in man study. Its main purpose is to establish a safe dosage of the drug and provide additional information on any potential side effects this drug may cause. The study will also assess the blood levels and action of AZD1480 in the body over a period of time and will indicate whether the drug has a therapeutic effect on myeloproliferative diseases.

开始日期2009-05-01

申办/合作机构

AstraZeneca PLC

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100 项与 AZD-1480 相关的临床结果

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100 项与 AZD-1480 相关的转化医学

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100 项与 AZD-1480 相关的专利（医药）

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项与 AZD-1480 相关的文献（医药）

2024-03-01·JOR spine

M1 macrophage‐derived oncostatin M induces osteogenic differentiation of ligamentum flavum cells through the JAK2/STAT3 pathway

Article

作者: Qu, Xiaochen ; Yang, Jun ; Fan, Tianqi ; Chen, Guanghui

Abstract:

Background:

M1 macrophages (Mφs) are involved in osteogenic differentiation of ligamentum flavum (LF) cells and play an important role in heterotopic ossification. However, the mechanism by which M1 Mφs influence osteogenic differentiation of LF cells has not been studied.

Methods:

The effect of conditioned medium including secretions of M1 Mφs (CM‐M1) on LF cells was analyzed by GeneChip profiling and ingenuity pathway analysis (IPA). THP‐1 cells were polarized into M1 Mφs and CM‐M1 was used to induce LF cells. In addition, LF cells were induced by CM‐M1 in the presence of cyclooxygenase 2 (COX‐2) inhibitors or oncostatin M (OSM)‐neutralizing antibodies. Based on the presence of OSM, knockout of OSMR or GP130 receptors, or addition of the Janus kinase 2 (JAK2) inhibitor AZD1480 or signal transducer and activator of transcription 3 (STAT3) inhibitor Stattic were examined for effects on osteogenic differentiation of LF cells. OSM secretion was quantified by ELISA, while qPCR and western blot were used to evaluate expression of osteogenic genes and receptor and signaling pathway‐related proteins, respectively.

Results:

GeneChip and IPA results indicate that the OSM signaling pathway and its downstream signaling molecules JAK2 and STAT3 are significantly activated. ELISA results indicate that OSM is highly expressed in cells treated with CM‐M1 and lowly expressed in cells treated with CM‐M1 and a COX‐2 inhibitor. Besides, CM‐M1 induces osteogenic differentiation of LF cells, which is weakened when COX‐2 inhibitors or OSM‐neutralizing antibody are added to it. Recombinant OSM could induce osteogenic differentiation of LF cells and upregulate expression of OSMR, GP130, phosphorylated (P)‐JAK2, and P‐STAT3. Upon knockdown of OSMR or GP130, or the addition of AZD1480 or Stattic, P‐JAK2 and P‐STAT3 expression were decreased and osteogenic differentiation was reduced.

Conclusion:

M1 Mφ‐derived OSM induces osteogenic differentiation of LF cells and the JAK2/STAT3 signaling pathway plays an important role.

2024-02-01·Kidney international reports

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy

Article

作者: Green, Todd J ; Huang, Zhi-Qiang ; Suzuki, Hitoshi ; Reily, Colin ; Novak, Jan ; Yamada, Koshi ; Suzuki, Yusuke

Introduction:

Galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy has been beneficial to some patients with IgAN, possibly due to the removal of tonsillar cytokine-activated cells producing Gd-IgA1. To test this hypothesis, we used immortalized IgA1-producing cell lines derived from tonsils of patients with IgAN or obstructive sleep apnea (OSA) and assessed the effect of leukemia inhibitory factor (LIF) or oncostatin M (OSM) on Gd-IgA1 production.

Methods:

Gd-IgA1 production was measured by lectin enzyme-linked immunosorbent assay; JAK-STAT signaling in cultured cells was assessed by immunoblotting of cell lysates; and validated by using small interfering RNA (siRNA) knock-down and small-molecule inhibitors.

Results:

IgAN-derived cells produced more Gd-IgA1 than the cells from patients with OSA, and exhibited elevated Gd-IgA1 production in response to LIF, but not OSM. This effect was associated with dysregulated STAT1 phosphorylation, as confirmed by STAT1 siRNA knock-down. JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction. Unexpectedly, high concentrations of AZD1480, but only in the presence of LIF, reduced Gd-IgA1 production in the cells derived from patients with IgAN to that of the control cells from patients with OSA. Based on modeling LIF-LIFR-gp130-JAK2 receptor complex, we postulate that LIF binding to LIFR may sequester gp130 and/or JAK2 from other pathways; and when combined with JAK2 inhibition, enables full blockade of the aberrant O-glycosylation pathways in IgAN.

Conclusion:

In summary, IgAN cells exhibit LIF-mediated overproduction of Gd-IgA1 due to abnormal signaling. JAK2 inhibitors can counter these LIF-induced effects and block Gd-IgA1 synthesis in IgAN.

2023-11-01·Journal of cancer research and clinical oncology

High-dose radiation-resistant lung cancer cells stored many functional lipid drops through JAK2/p-STAT3/FASN pathway.

Article

作者: Zhu, Xiaoxia ; Qiao, Simiao ; Yang, Ting

BACKGROUND:

The understanding of radiation resistance is still unclear. This study aims to explore the new mechanism of radiation resistance in lung cancer from the perspective of lipid metabolism.

METHODS:

Oil red O was used to detect the amount of lipid droplets in high-dose radiation-resistant lung cancer cells (HDRR-LCCs) and the primary lung cancer cells. Western blot analysis was used to determine the protein expression levels of key molecules related to de novo fatty acid synthesis and fatty acid transport. Orlistat was used to inhibit the de novo fatty acid synthesis. The prediction of the transcriptional regulators of fatty acid synthetase (FASN) was analyzed by bioinformatics. AZD-1480 was used to inhibit the JAK2/STAT3 pathway to observe its effects on FASN and intracellular lipid droplets. The regulation of the transcription factor p-STAT3 on the FASN gene was verified by Chip-qPCR. Finally, we used the public data of lung cancer patients to analyze the correlation between FASN and LPL gene expression with the prognosis.

RESULTS:

There were more lipid drops in the HDRR-LCCs than in the primary lung cancer cells. HDRR-LCCs preferred de novo synthesis of fatty acids, and high expression of LPL homodimers indicated a high intake of extracellular fatty acids. The expression of FASN was increased in HDRR-LCCs compared with the primary lung cancer cells in a radiation-dose-dependent way, while LPL homodimers did not show such a trend. The lipid droplets, cell proliferation, and radiation resistance were decreased in HDRR-LCCs after orlistat treatment. Lipid droplets were significantly reduced, and the protein expression of FASN also decreased when using AZD-1480 to inhibit the JAK2/STAT3 pathway. The Chip-qPCR showed that p-STAT3 was the upstream regulator which binds to the promoter region of FASN. Survival analysis showed that high expression of the FASN gene was associated with a poor prognosis in lung cancer patients who received radiotherapy.

CONCLUSION:

Our studies discovered that lipids deposited in HDRR-LCCs were due to endogenous de novo fatty acids synthesis and exogenous lipids uptake. JAK2/p-TAT3/FASN could be used as promising targets for radiotherapy sensitization. Our study provided a new theoretical basis for studying the mechanism of radiation resistance in lung cancer.

项与 AZD-1480 相关的新闻（医药）

2024-06-21

·奇点网

JAK抑制剂们是要打开一片全新的战场啦

*仅供医学专业人士阅读参考看到今天最新一期《科学》的两篇论文标题，奇点糕只能用一句话总结心里的感受——“柳暗花明又一村”：科学界这次给免疫治疗找来的帮手可实在是绝了，JAK抑制剂都来了？它们的主业不是抑制免疫细胞异常激活，用于治疗某些免疫相关性疾病么？这是怎么个事儿？没错，JAK抑制剂真就能增效免疫治疗。美国明尼苏达大学和Scripps研究所团队利用高通量筛选发现，JAK抑制剂能将髓系细胞从免疫抑制逆转为免疫刺激状态，从而有效挽救耗竭T细胞功能，并在一项用于免疫治疗难治/复发性霍奇金淋巴瘤患者的临床I期研究中表现良好，客观缓解率（ORR）为53%，且患者2年总生存率（OS）高达87%[1]。 JAK抑制剂调节髓系细胞，增敏免疫治疗的机制概括而在宾夕法尼亚大学研究者们同期开展的另一项研究中，JAK1抑制剂则通过阻断持续存在的I型干扰素（IFN-I）信号，改善了T细胞分化状态和功能，且在临床II期研究中联合PD-1抑制剂一线治疗晚期非小细胞肺癌（NSCLC）的ORR高达67%，患者中位无进展生存期（mPFS）长达23.8个月，是现有免疫一线治疗水平的2-3倍[2]！如果能把握好用药时机，并精准选出最具免疫刺激性的药物，JAK抑制剂绝对有希望成为免疫治疗的强援。虽说JAK抑制剂此前的用途主要是通过抑制免疫反应，治疗类风湿关节炎、银屑病等各种自身免疫性或者叫“免疫介导性疾病”，但JAK抑制剂主要调控的JAK-STAT通路在人体内影响范围非常广阔，所以在一些临床前研究中，JAK抑制剂还真就体现了抑癌效应[3]，但搞不清楚作用机制，临床医生们也不敢贸然尝试用药，但有了这次研究的成果就不同了。奇点糕先说说明尼苏达大学和Scripps研究所团队的研究，该研究使用淋巴细胞性脉络丛脑膜炎病毒（LCMV Cl13）慢性感染小鼠免疫抑制模型，配合高通量筛选技术在约1.2万个生物活性物质中，寻找能挽救T细胞耗竭的分子靶点，而筛选结果中就集中了多种JAK抑制剂，其中抑制JAK1和/或JAK2的芦可替尼（ruxolitinib）等药物作用最为明显。研究者们选择用已获批上市的JAK1/2抑制剂芦可替尼展开进一步实验，发现它对CD8+T细胞的激活效果甚至优于PD-L1抑制剂，并影响肿瘤微环境中的髓系细胞、自然杀伤（NK）细胞和树突状细胞（DCs），还不会对T细胞抗病毒感染的效应功能产生负面影响，从而在荷瘤小鼠模型中与PD-1抑制剂±CTLA-4抑制剂的免疫治疗实现协同增效。而受JAK抑制剂影响最大的，就是浸润到肿瘤的髓系来源免疫抑制细胞（MDSCs），它们的数量和免疫抑制功能都明显下降，实验显示，JAK抑制剂使这些细胞发生了显著的重编程，各种MDSCs功能相关标志物的表达都大幅下降，MHC-II类分子表达反而大增，意味着这些细胞具有了向T细胞呈递抗原、激活免疫应答的能力，真就化敌军为友军了。 JAK抑制剂使MDSCs发生有利于抗癌免疫应答的重编程基于上述发现，研究者们设计了一项以芦可替尼配合PD-1抑制剂（纳武利尤单抗）用于免疫检查点抑制剂治疗失败霍奇金淋巴瘤患者的临床I期研究，患者在每个治疗周期开始时先使用芦可替尼，8天后再接受纳武利尤单抗治疗，治疗的整体ORR达到53%，且有6例完全缓解，患者2年PFS和OS率分别为46%和87%；单细胞测序结果显示，芦可替尼治疗有效减少了患者体内的MDSCs数量，与此前研究探明的起效机制相符。芦可替尼配合PD-1抑制剂治疗霍奇金淋巴瘤患者的临床I期研究概况宾夕法尼亚大学研究团队在肺癌中开展的研究，则采用了不一样的用药方案——在免疫治疗7天后再使用JAK1抑制剂itacitinib，一线治疗NSCLC同样有极佳的疗效；后续机制探索发现，序贯使用JAK1抑制剂可以通过阻断持续激活的IFN-I信号，减少CD8+T细胞向耗竭和终末状态分化，并改善细胞可塑性，从而使CD8+T细胞更好地响应免疫治疗。免疫治疗+JAK1抑制剂一线治疗NSCLC的临床II期研究概况《科学》同期发表的社论文章指出，JAK抑制剂联合免疫治疗的良好初步疗效，似乎破解了它们作为“免疫抑制剂”配合免疫治疗的悖论，但也不能只顾着挽救耗竭T细胞，而忽略了抑制JAK-STAT通路对抗肿瘤免疫的潜在不利影响，毕竟免疫系统还是太复杂啦，不同JAK抑制剂的靶点选择性是否会影响协同增效，就看未来的研究能不能给出答案了。参考文献： [1]Zak J, Pratumchai I, Marro B S, et al. JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma[J]. Science, 384(6702): eade8520. [2]Mathew D, Marmarelis M E, Foley C, et al. Combined JAK inhibition and PD-1 immunotherapy for non–small cell lung cancer patients[J]. Science, 384(6702): eadf1329. [3]Maenhout S K, Du Four S, Corthals J, et al. AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells[J]. Oncotarget, 2014, 5(16): 6801-6815. 本文作者丨谭硕

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100 项与 AZD-1480 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12588

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肝细胞癌	临床2期	-	阿斯利康制药有限公司	-
骨髓增生性疾病	临床2期	美国	AstraZeneca PLC	-
骨髓增生性疾病	临床2期	法国	AstraZeneca PLC	-
原发性骨髓纤维化	临床2期	-	阿斯利康制药有限公司	-
晚期肝细胞癌	临床1期	韩国	AstraZeneca PLC	2010-11-01
胃癌	临床1期	韩国	AstraZeneca PLC	2010-11-01
晚期恶性实体瘤	临床1期	美国	AstraZeneca PLC	2010-04-01
非小细胞肺癌	临床1期	美国	AstraZeneca PLC	2010-04-01
继发性肺恶性肿瘤	临床1期	美国	AstraZeneca PLC	2010-04-01
骨髓增生异常/骨髓增生性疾病	临床1期	美国	AstraZeneca PLC	2009-05-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00910728 (CTgov)	临床1期	真性红细胞增多症 \| 骨髓增生异常/骨髓增生性疾病 \| 原发性血小板增多症 ... 更多	65	AZD1480 (2.5 mg QD)	憲鏇餘壓獵鹽鬱鏇窪觸(壓鏇鬱築齋憲範襯繭觸) = 鏇淵積壓糧遞獵糧鹽顧簾選鬱艱餘願鑰艱壓衊 (餘齋製範糧襯鬱範願窪, 網築淵觸糧製膚範餘鹽 ~ 壓鬱願鬱夢廠獵網觸憲) 更多	-	2017-04-24
NCT00910728 (CTgov)	临床1期	真性红细胞增多症 \| 骨髓增生异常/骨髓增生性疾病 \| 原发性血小板增多症 ... 更多	65	AZD1480 (5.0 mg QD)	憲鏇餘壓獵鹽鬱鏇窪觸(壓鏇鬱築齋憲範襯繭觸) = 鹹蓋築構夢餘積繭範顧簾選鬱艱餘願鑰艱壓衊 (餘齋製範糧襯鬱範願窪, 積醖憲鏇範顧鹽醖艱蓋 ~ 鏇鹽艱鑰製醖遞糧糧窪) 更多	-	2017-04-24
AACR2012	临床2期	肿瘤 \| 神经母细胞瘤	-	AZD1480	窪鬱築遞衊襯選網淵膚(壓鹹壓淵襯鑰網襯窪壓) = 鬱憲製製壓衊糧鏇網鑰簾鹽艱餘膚鬱鏇築夢糧 (網窪願願襯選積簾膚鹽 )	-	2012-04-15