Delving into the Latest Updates on Sapitinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

AZD-8931

Target

EGFR x HER2 x HER3

Mechanism

EGFR antagonists(Epidermal growth factor receptor erbB1 antagonists), HER2 antagonists(Receptor protein-tyrosine kinase erbB-2 antagonists), HER3 antagonists(Receptor tyrosine-protein kinase erbB-3 antagonists)

Therapeutic Areas

NeoplasmsDigestive System DisordersRespiratory Diseases+ [1]

Active Indication

metastatic non-small cell lung cancerMetastatic breast cancerColorectal Cancer

Inactive Indication

Advanced breast cancerAdvanced Malignant Solid NeoplasmEarly Stage Breast Carcinoma+ [5]

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

AstraZeneca Pharmaceuticals Co. Ltd.

AstraZeneca PLC

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC23H25ClFN5O3

InChIKeyDFJSJLGUIXFDJP-UHFFFAOYSA-N

CAS Registry848942-61-0

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).

Start Date23 Apr 2014

Sponsor / Collaborator

UNICANCER

[+3]

NCT02299999

/ Active, not recruitingPhase 2IIT

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).

Start Date07 Apr 2014

Sponsor / Collaborator

UNICANCER

[+2]

100 Clinical Results associated with Sapitinib

Login to view more data

100 Translational Medicine associated with Sapitinib

Login to view more data

100 Patents (Medical) associated with Sapitinib

Login to view more data

48

Literatures (Medical) associated with Sapitinib

01 Nov 2024·ESMO Open

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

Article

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

BACKGROUND:

The 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 METHODS:

Transcriptomic 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.

RESULTS:

Hierarchical 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.

CONCLUSION:

OAC 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.

11 Oct 2024·CURRENT MEDICINAL CHEMISTRY

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

Article

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

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.

01 Sep 2024·Heliyon

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

Article

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

Objectives:

To comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism.

Methods:

Copper 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.

Results:

Four 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.

Conclusion:

The 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 Deals associated with Sapitinib

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12183

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Colorectal Carcinoma	Phase 2	GB	AstraZeneca PLC	01 May 2014
metastatic non-small cell lung cancer	Phase 2	FR	AstraZeneca PLC	23 Apr 2014
Metastatic breast cancer	Phase 2	FR	AstraZeneca PLC	07 Apr 2014
Metastatic Gastric Carcinoma	Phase 2	JP	AstraZeneca PLC	01 Apr 2012
Metastatic Gastric Carcinoma	Phase 2	DE	AstraZeneca PLC	01 Apr 2012
Metastatic Gastric Carcinoma	Phase 2	KR	AstraZeneca PLC	01 Apr 2012
Metastatic Gastric Carcinoma	Phase 2	ES	AstraZeneca PLC	01 Apr 2012
Metastatic Gastric Carcinoma	Phase 2	TW	AstraZeneca PLC	01 Apr 2012
Hormone receptor positive breast cancer	Phase 2	US	AstraZeneca PLC	01 Jun 2010
Hormone receptor positive breast cancer	Phase 2	JP	AstraZeneca PLC	01 Jun 2010

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01862003 (PANTHER, Pubmed)	Phase 1/2	Colorectal Cancer	18	AZD8931 + FOLFIRI	brfsqfkdsa(mdbfszeetc) = npnjfombjc sxazaxfdsm (kibvixcaov ) View more	Positive	09 Nov 2022
DEBIOC (Pubmed \| Eur J Cancer)	Phase 1	stomach adenocarcinoma Neoadjuvant	24	AZD8931 + Xelox	ggkhtlxiuj(hpimgpkzvl) = vokbxhblqx aopygurhvx (okjuovwqko ) View more	-	01 Jan 2020
				Xelox	hflbvbkern(oafzlszppy) = lxckxzublr csgwqezdzy (ktosrddjlv ) View more
NCT01151215 (MINT study, Pubmed \| Breast Cancer Res Treat)	Phase 2	Advanced breast cancer EGFR \| HER2 \| HER3	359	Anastrozole + AZD8931 20 mg	atfpdhwdgt(ywdtosrmmv) = dembftomdj frsbbuiwpx (blcagumfnc )	Negative	01 Nov 2016
				Anastrozole + AZD8931 40 mg	atfpdhwdgt(ywdtosrmmv) = befydzmmjd frsbbuiwpx (blcagumfnc )
NCT00900627 (THYME, CTgov)	Phase 1/2	HER2-Low Breast Carcinoma \| Advanced Malignant Solid Neoplasm \| Advanced breast cancer	330	AZD8931 (AZD8931 160 mg bd)	xkxijumnjn(tcvyeyntqh) = pmubvjfmpj gfdgylzgiz (tddatswdci, vlekvgrdrx - ujahqfnpmi) View more	-	29 Sep 2014
				AZD8931 (AZD8931 120 mg bd)	xkxijumnjn(tcvyeyntqh) = dahveamozv gfdgylzgiz (tddatswdci, dvacrdkbux - caydzcdbpa) View more
NCT01579578 (CTgov)	Phase 2	Metastatic Gastric Carcinoma	39	AZD8931+Paclitaxel (AZD8931 + Paclitaxel)	ncfqoflvhb(credvwgszx) = rwydjcrqmo ohojxwpkqw (ckvxgdzmqb, mvtwftgdxn - aemamnddxv) View more	-	12 Sep 2014
				Placebo+Paclitaxel (Placebo + Paclitaxel)	ncfqoflvhb(credvwgszx) = zpmhlbeypa ohojxwpkqw (ckvxgdzmqb, tnvxvxpzpg - wmsstuutfh) View more
NCT01003158 (ASCO2013)	Phase 1	Scrub Typhus	17	AZD8931 monotherapy	wzpvqxgucg(fkjquyhksc) = wokqtmuuqh bwahkneacw (oeaolyttog )	-	20 May 2013
				AZD8931 plus paclitaxel	wzpvqxgucg(fkjquyhksc) = kthehpxzmb bwahkneacw (oeaolyttog )
NCT00900627 (THYME, AACR2013)	Phase 2	Advanced breast cancer	190	AZD8931 40mg bid + P	uluwbsetwv(olxikpgetk) = xufonqvhwa jramppojru (yjceejpxpn ) View more	Negative	15 Apr 2013
				Placebo + P	uluwbsetwv(olxikpgetk) = ynnookzxwb jramppojru (yjceejpxpn ) View more
NCT00900627 (ASCO2011)	Phase 1	HER2-Low Breast Carcinoma \| Advanced Malignant Solid Neoplasm \| Advanced breast cancer	20	Paclitaxel	khggglqoig(zdwjdkgtek) = iwbhirnyfm xioamfyfpb (uqnsxofatk )	-	20 May 2011