Sapitinib(Sapitinib) - 药物靶点：EGFR x HER2 x HER3_在研适应症：结直肠癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

EGFR x HER2 x HER3

作用机制

EGFR拮抗剂(表皮生长因子受体erbB1拮抗剂)、HER2拮抗剂(受体蛋白酪氨酸激酶 erbB-2拮抗剂)、HER3拮抗剂(受体酪氨酸蛋白激酶erbB-3拮抗剂)

治疗领域

肿瘤消化系统疾病

在研适应症

结直肠癌

非在研适应症

晚期乳腺癌晚期恶性实体瘤早期乳腺癌+ [5]

原研机构

阿斯利康制药有限公司

在研机构

阿斯利康制药有限公司

非在研机构

AstraZeneca PLC

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C23H25ClFN5O3

InChIKeyDFJSJLGUIXFDJP-UHFFFAOYSA-N

CAS号848942-61-0

关联

14

项与 Sapitinib 相关的临床试验

NCT01862003 / Completed临床2期IIT

AZD8931, an Inhibitor of EGFR, ERBB2 and ERBB3 Signalling, in Combination With FOLFIRI: a Phase I/II Study to Determine the Importance of Schedule and Activity in Colorectal Cancer

Recruitment to phase I of the PANTHER trial is complete.
Phase II, is to evaluate the best overall response rate for AZD8931 + FOLFIRI treatment.

开始日期2014-05-01

申办/合作机构

University College London

[+3]

NCT02117167 / Completed临床2期IIT

Intergroup Trial UNICANCER UC 0105-1305/ IFCT 1301: SAFIR02_Lung - Evaluation of the Efficacy of High Throughput Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Non-small Cell Lung Cancer

Open label multicentric randomized phase II trial, using high throughput genome analysis as a therapeutic decision tool, aimed at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with a standard treatment (pemetrexed in Non-squamous patients and erlotinib in squamous cells, targeted substudy 1) as well as immunotherapy with maintenance therapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2).

开始日期2014-04-23

申办/合作机构

UNICANCER

[+3]

NCT02299999 / Active, not recruiting临床2期IIT

PERSONALIZED MEDICINE GROUP / UCBG UC-0105/1304: SAFIR02_Breast - Evaluation of the Efficacy of High Throughput Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer

Open label multicentric phase II randomized trial, using high throughput genome analysis as a therapeutic decision tool, which aims at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with maintenance chemotherapy (targeted substudy 1) as well as immunotherapy with maintenance chemotherapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2).

开始日期2014-04-07

申办/合作机构

UNICANCER

[+2]

100 项与 Sapitinib 相关的临床结果

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100 项与 Sapitinib 相关的转化医学

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100 项与 Sapitinib 相关的专利（医药）

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45

项与 Sapitinib 相关的文献（医药）

2024-11-01·ESMO Open

Immune microenvironment modulation following neoadjuvant therapy for oesophageal adenocarcinoma: a translational analysis of the DEBIOC clinical trial

Article

作者: Eatock, M M ; Van Schaeybroeck, S ; Miedzybrodzka, Z. ; Byrne, R. ; Elhussein, L ; Turbitt, J ; Eatock, M.M. ; James, J.A. ; Virdee, P S ; McQuaid, S ; James, J A ; Van Schaeybroeck, S. ; Walker, A. ; Turkington, R C ; Petty, R.D. ; Petty, R D ; Kennedy, R.D. ; Kennedy, C. ; Byrne, R ; Harkin, D P ; Collinson, D ; Walker, A ; Kennedy, R D ; Scanlon, E. ; Craig, S.G. ; Collinson, D. ; Blayney, J.K. ; McManus, D.T. ; Turkington, R.C. ; Mullan-Young, B ; Harkin, D.P. ; Mullan-Young, B. ; Virdee, P.S. ; Albraikat, M. ; Lavery, A. ; Middleton, M R ; Thomas, A. ; Craig, S G ; Middleton, M.R. ; Stevenson, L. ; Blayney, J K ; McManus, D T ; Turbitt, J. ; Stevenson, L ; Kennedy, C ; Miedzybrodzka, Z ; Thomas, A ; McQuaid, S. ; Elhussein, L. ; Scanlon, E ; Albraikat, M ; Lavery, A

BACKGROUNDThe Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant oxaliplatin and capecitabine (Xelox) ± AZD8931 in oesophageal adenocarcinoma (OAC) but limited efficacy. We evaluated the impact of neoadjuvant Xelox ± AZD8931, a novel small-molecule inhibitor with equipotent activity against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2 and HER3, on biological pathways using a unique software-driven solution.PATIENTS AND METHODSTranscriptomic profiles from 25 pre-treatment formalin-fixed paraffin-embedded OAC biopsies and 18 matched resection specimens, treated with Xelox + AZD8931 (n = 16) and Xelox alone (n = 9), were analysed using the Almac clara^T total mRNA report analysing 92 gene signatures, 100 unique single-gene drug targets and 7337 single genes across 10 hallmarks of cancer. Gene-set enrichment analysis (GSEA) was utilised to investigate pathways governing pathological response. Tumour-infiltrating lymphocytes (TILs) were assessed digitally using the QuPath software.RESULTSHierarchical clustering identified three molecular subgroups classified by activation of innate immune signalling. The immune-high subgroup was associated with HER2 positivity, increased pathological response and a marked reduction in immune signalling and TILs following neoadjuvant therapy. The immune-low cluster was predominantly HER2/EGFR-negative, and EGFR positivity was associated with the immune-mixed subgroup. Treatment with neoadjuvant therapy induced common resistance mechanisms, such as angiogenesis and epithelial-mesenchymal transition signalling, and a reduction in DNA repair signatures. Addition of AZD8931 was associated with reduction of expression of EGFR, HER2 and AKT pathways and also promoted an immunosuppressive microenvironment. GSEA showed that patients with a pathological response to treatment had increased immune signalling, whereas non-responders to neoadjuvant therapy were enriched for nucleotide repair and cellular growth through the action of E2F transcription factors.CONCLUSIONOAC may be subdivided into three immune-related subgroups which undergo modulation in response to neoadjuvant therapy with marked suppression of the immune microenvironment in HER2-positive/immune-high tumours.

2024-10-11·Current Medicinal Chemistry

FOXN3-AS1: A Candidate Prognostic Marker and Epigenetic Target with Immunotherapeutic Implications in Acute Myeloid Leukemia

Article

作者: Schmidt-Wolf, Ingo G.H. ; Ge, Fangfang ; Huang, Xiaoli ; Wang, Yulu ; Wang, Zifeng ; Chen, Peng ; Sharma, Amit ; Dakal, Tikam Chand ; Essler, Markus ; Jaehde, Ulrich ; Schmid, Matthias

Aim:We focused on the FOXN3 gene and selected its antisense transcripts (FOXN3-AS1) to investigate its potential involvement in acute myeloid leukemia (AML).Background:Several integrated multi-omics datasets have expanded the horizons of the cancer landscape. With the emergence of new high-throughput technologies, a large number of non-coding RNAs have been confirmed to be involved in the pathogenesis of different types of hematological malignancies.Methods:We conducted experimental validation using quantitative polymerase chain reaction (qPCR) with bone marrow specimens from AML patients. Then, Kaplan-Meier (KM) and Receiver Operating Characteristic (ROC) curves were used to substantiate the prognostic association between FOXN3-AS1 and AML patients within the TCGA database. Correlation between FOXN3-AS1 expression and gene mutation, immune, and immune function using Spearman correlation analysis. To explore the physical and functional interaction between FOXN3-AS1 and the DNMT1 protein, we utilized the RPISeq web tool from Iowa State University. Subsequently, we performed qPCR experiments to test the effect of 5AzaC (DNMT1 inhibitor) on FOXN3-AS1 expression AML cell lines (THP1 and OCI-AML3). We leveraged the “OncoPredict” R package in conjunction with the Genomics of Drug Sensitivity (GDSC) database to predict drug response in AML patients expressing FOXN3-AS1.Results:We observed a significant upregulation of FOXN3-AS1 expression in AML patients compared to healthy controls using clinical samples. The TCGA database revealed an association between high FOXN3-AS1 expression and adverse prognosis. In our subsequent analysis, genes with poor prognostic implications in AML patients were exclusively identified in the FOXN3-AS1 high-expression group, further corroborating this relationship. AML patients with higher FOXN3-AS1 expression levels may respond less optimally to immunotherapy than patients with lower levels. Besides, we computationally predicted the interaction of FOXN3- AS1 and DNMT1 protein and experimentally confirmed that DNMT1i (GSK-3484862) affects the expression level of FOXN3-AS1. We also found that the chemotherapy drugs (5-Fluorouralic, Cisplatin, Dactolisib, Sapitinib, Temozolomide, Ulixertinib, Vinorelbine, Ruxolitinib, Osimertinib and Cisplatin) showed favorable responses in AML patients with high FOXN3-AS1 expression levels.Conclusion:Our candidate approach identifies FOXN3-AS1 as a prognostic indicator of survival in AML with a potential immune-related role. The preliminary observations we made on FOXN3-AS1/DNMT1 crosstalk warrant more in-depth invested immunotherapeutic approaches in AML.

2024-09-01·Heliyon

Copper metabolism–related signature for prognosis prediction and MMP13 served as malignant factor for breast cancer

Article

作者: Xu, Shoufang ; Hu, Mengsi ; Liu, Zhiwei ; Han, Chaojie ; Li, Yunsen ; Feng, Zhangyang ; Jiang, Feiyu ; Wang, Yingjian ; Han, Yetao

ObjectivesTo comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism.MethodsCopper metabolism-related genes were sourced from previous literatures and were selected by the Univariate Cox regression. Cu-enrichment scores were calculated via ssGSEA. Differentially expressed genes were identified with limma between high and low Cu-enrichment scores group, then we used the Random Survival Forest and LASSO to build the CuScore for BC. Kaplan-Meier analysis, ROC curves, and Cox regression were used to evaluate CuScore. Genomic mutations were analyzed with GISTIC. Immune cells were examined using ESTIMATE, ssGSEA and TIMER. Enrichment analysis used clusterProfiler and GSVA. The GDSC database and oncoPredict package analyzed chemotherapeutic sensitivity. MMP13 was selected for in vitro assays.ResultsFour copper metabolism-related genes (UBE2D2, SLC31A1, ATP7A, and MAPK1) with prognostic value were identified. Higher expression levels of these genes were associated with higher Cu-enrichment scores, a factor of malignancy in breast cancer. Among 115 differentially expressed genes, 19 prognostic genes were identified, with three (CEACAM5, MMP13, and CRISP3) highlighted by Random Survival Forest and LASSO. Higher CuScores correlated with worse prognoses and were effective in predicting breast cancer outcomes. CuScore and metastasis were independent prognostic factors. Tumor-infiltrating immune cells were associated with lower CuScores. GO-GSEA analysis indicated six immune-related pathways might be regulated by CuScore. Patients with higher CuScores had lower TMB and were more sensitive to Sapitinib and LCL161, while those with lower CuScores might respond better to anti-PD1 therapy. High MMP13 expression in breast cancer was linked to malignancy, affecting cell proliferation and migration.ConclusionThe identified copper metabolism-related gene signature has the potential to predict prognosis and guide clinical treatment for BC. Among these genes, MMP13 may act as a malignant factor in BC.

100 项与 Sapitinib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12183

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
结直肠癌	临床2期	-	阿斯利康制药有限公司	-
晚期恶性实体瘤	药物发现	意大利	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	捷克	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	比利时	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	巴拿马	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	法国	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	匈牙利	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	西班牙	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	加拿大	AstraZeneca PLC	2009-06-01
晚期恶性实体瘤	药物发现	英国	AstraZeneca PLC	2009-06-01

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临床结果

适应症

分期

评价

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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


NCT01862003 (PANTHER, Pubmed)	临床1/2期	结直肠癌	18	AZD8931 + FOLFIRI	(觸遞顧醖願糧醖遞積鹹) = 鑰網憲繭餘衊齋糧構壓蓋蓋鹹憲襯醖蓋糧鹽鏇 (憲選蓋積糧糧選蓋繭夢 ) 更多	积极	2022-11-09
DEBIOC (Pubmed \| Eur J Cancer Care (Engl))	临床1期	腺癌新辅助	24	AZD8931 + Xelox	(壓壓齋衊蓋簾築範壓觸) = 築構觸醖壓選醖築顧鹽壓築憲獵艱範簾窪衊積 (窪簾艱鬱廠鬱壓醖鏇簾 ) 更多	-	2020-01-01
				Xelox	(憲遞製繭願窪餘繭憲網) = 糧獵艱鏇觸憲膚鏇製廠鹽築鹹憲夢鏇鹹範醖範 (鏇艱範網糧衊網獵範製 ) 更多
NCT01151215 (MINT, Pubmed \| Breast Cancer Res)	临床2期	晚期乳腺癌	359	Anastrozole + AZD8931 20 mg	(醖範選齋糧鬱壓範艱窪) = 醖網願淵窪糧構餘築廠淵鹽淵願選憲餘繭憲獵 (網糧窪衊構鏇夢憲艱繭 )	不佳	2016-11-01
				Anastrozole + AZD8931 40 mg	(醖範選齋糧鬱壓範艱窪) = 繭醖獵淵壓憲網襯獵餘淵鹽淵願選憲餘繭憲獵 (網糧窪衊構鏇夢憲艱繭 )
NCT00900627 (THYME, CTgov)	临床1/2期	HER2低表达乳腺癌 \| 晚期恶性实体瘤 \| 晚期乳腺癌	330	AZD8931 (AZD8931 160 mg bd)	壓夢廠憲夢簾膚襯憲廠(餘範餘廠簾鏇網夢鏇醖) = 選遞製淵鏇鑰簾鏇遞鑰齋顧醖遞觸構醖範網艱 (艱觸糧廠膚鏇襯顧壓襯, 製窪憲夢壓餘蓋憲製淵 ~ 選製衊齋願壓糧糧選膚) 更多	-	2014-09-29
				AZD8931 (AZD8931 120 mg bd)	壓夢廠憲夢簾膚襯憲廠(餘範餘廠簾鏇網夢鏇醖) = 築築膚壓淵簾艱顧齋膚齋顧醖遞觸構醖範網艱 (艱觸糧廠膚鏇襯顧壓襯, 齋窪獵鏇廠廠築餘鹽遞 ~ 鬱鏇遞齋觸積製餘艱艱) 更多
NCT01579578 (CTgov)	临床2期	转移性胃癌	39	AZD8931+Paclitaxel (AZD8931 + Paclitaxel)	簾壓鑰鏇顧艱餘窪遞衊(築顧願淵鹹糧鑰願憲構) = 憲齋遞鏇憲簾顧顧憲遞鹹蓋鬱艱鬱網淵齋窪餘 (網壓齋餘製蓋鏇齋糧醖, 鹹衊憲餘築鏇窪膚餘遞 ~ 憲築簾齋鑰網鏇窪積餘) 更多	-	2014-09-12
				Placebo+Paclitaxel (Placebo + Paclitaxel)	簾壓鑰鏇顧艱餘窪遞衊(築顧願淵鹹糧鑰願憲構) = 選願願憲鹹醖餘鏇顧糧鹹蓋鬱艱鬱網淵齋窪餘 (網壓齋餘製蓋鏇齋糧醖, 鹽築鑰淵壓範齋襯遞齋 ~ 襯壓齋憲壓簾夢壓製鹹) 更多
NCT01003158 (ASCO2013)	临床1期	恙虫病	17	AZD8931 monotherapy	淵糧艱選壓繭製餘製積(獵鏇憲窪製構窪顧衊醖) = 餘窪齋夢壓網鏇淵簾淵鬱簾廠構餘製憲蓋網鹹 (壓鏇鬱網鏇製鏇願積顧 )	-	2013-05-20
				AZD8931 plus paclitaxelAZD8931 plus paclitaxel	淵糧艱選壓繭製餘製積(獵鏇憲窪製構窪顧衊醖) = 蓋鬱壓遞鏇鏇糧憲鏇鹽鬱簾廠構餘製憲蓋網鹹 (壓鏇鬱網鏇製鏇願積顧 )