Delving into the Latest Updates on Sapitinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

EGFR x HER2 x HER3

Action

antagonists

Mechanism

EGFR antagonists(Epidermal growth factor receptor erbB1 antagonists), HER2 antagonists(Receptor tyrosine-protein 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-

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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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

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100 Translational Medicine associated with Sapitinib

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100 Patents (Medical) associated with Sapitinib

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135

Literatures (Medical) associated with Sapitinib

01 Dec 2024·Molecular Genetics and Genomics

A comprehensive genome-based analysis identifies the anti-cancerous role of the anoikis-related gene ADH1A in modulating the pathogenesis of breast cancer

Article

Author: Rao, Haishan ; Guo, Shan ; Chen, Guimin ; Yang, Jun ; Yang, Ying ; Ma, Yun ; Chai, Wenying ; Chen, Cheng ; Bai, Song

Breast cancer (BC), a widespread and lethal neoplasm, is irrespective of the subtype of BC. Metastasis remains a crucial determinant for unfavorable outcome. The identification of novel diagnostic markers is instrumental in optimizing the treatment regime for BC. The direct correlation between anoikis and the progression/outcome of BC is well established. Nevertheless, the contribution of anoikis-related genes (ARGs) in BC remains obscure at present. We implemented the METABRIC dataset to scrutinize and assess differentially expressed ARGs in BC versus healthy breast tissues. An unsupervised consensus clustering approach for ARGs was employed to classify patients into diverse subtypes. ESTIMATE algorithms were utilized to assess immune infiltrative patterns. Prognostic gene expression patterns were derived from LASSO regression and univariate COX regression analysis. Subsequently, these signatures underwent examination via use of the Kaplan-Meier survival curve. 6 pairs of fresh tissue specimens (tumor and adjacent non-tumor) were employed to assess the expression of 7 ARGs genes via qPCR. Notably, DCN and FOS were not expressed in BC tissue, which had been excluded in our subsequent experiments. Also, among remaining 5 ARGs, solely the expression of ADH1A demonstrated a statistically remarkable disparity between freshly collected cancer tissues and the adjacent ones. ADH1A-overexpressed and ADH1A-sh vectors were transfected into MCF-7 and MCF-7-AR cell lines, respectively. The expression status of FABP4, CALML5, ADH1A, C1orf106, CIDEC, β-catenin, N-cadherin, and Vimentin in the clinical samples were scrutinized using RT-qPCR and western blotting techniques. Migration and invasion through transwell chambers were employed to assess the migratory and invasive potential of the cells. Detailed evaluation of cell proliferation was conducted utilizing a Cell Counting Kit-8 (CCK-8) assay. The apoptotic index of the cells was determined by flow cytometry analysis. An innovative anoikis-associated signature consisting of seven genes, namely ADH1A, DCN, CIEDC, FABP4, FOS, CALML5, and C1orf106, was devised to stratify BC patients into high- and low-risk cohorts. This unique risk assessment model, formulated via the distinctive signature approach, has been validated as an independent prognostic indicator. Additional analysis demonstrated that distinct risk subtypes manifested variances in the tumor microenvironment and drug sensitivities. Suppression of ADH1A enhanced the migratory and invasive capacities and reduced these tumorigenesis-related protein levels, underscoring the prognostic role of ADH1A in the progression of BC. Through our meticulous study, we have elucidated the possible molecular markers and clinical implications of ARGs in BC. Our model, which incorporate seven ARGs, has proven to accurately forecast the survival outcomes of BC patients. Moreover, the thorough molecular study of ADH1A has augmented our comprehension of ARGs in BC and opened a novel avenue for guiding personalized and precise therapeutic interventions for BC patients.

01 Nov 2024·ESMO Open

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

Article

Author: 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. ; Kennedy, R.D. ; Petty, R D ; Kennedy, C. ; Byrne, R ; Harkin, D P ; Walker, A ; Collinson, D ; 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. ; Craig, S G ; Middleton, M R ; Lavery, A. ; Thomas, A. ; 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.

11 Oct 2024·Current Medicinal Chemistry

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

Article

Author: 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.

100 Deals associated with Sapitinib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12183

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
HER2-Low Breast Carcinoma	Discovery	Czechia	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	France	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	Spain	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	Sweden	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	Italy	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	Bulgaria	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	Panama	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	Belgium	AstraZeneca PLC	01 Jun 2009
HER2-Low Breast Carcinoma	Discovery	Peru	AstraZeneca PLC	01 Jun 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01862003 (PANTHER, Pubmed)	Phase 1/2	Colorectal Cancer	18	AZD8931 + FOLFIRI	(gyzxzmsxra) = syeaoywxvf daiurzdlrn (kxzfhqujtn ) View more	Positive	09 Nov 2022
DEBIOC (Pubmed \| Eur J Cancer)	Phase 1	stomach adenocarcinoma Neoadjuvant	24	AZD8931 + Xelox	(rznsyduwzs) = fzjsdwcwep kqsggnqnej (jghniwbljb ) View more	-	01 Jan 2020
				Xelox	(whkszsajox) = mpkgjpzcxl cyqcvcubsd (uwuyqgxzih ) View more
NCT01151215 (MINT study, Pubmed \| Breast Cancer Res Treat)	Phase 2	Advanced breast cancer EGFR \| HER2 \| HER3	359	Anastrozole + AZD8931 20 mg	(wfpecjjjaf) = whrpbgkxew lvaaewrkgf (xnlddibhcw )	Negative	01 Nov 2016
				Anastrozole + AZD8931 40 mg	(wfpecjjjaf) = xgqjfgqhwe lvaaewrkgf (xnlddibhcw )
NCT00900627 (THYME, CTgov)	Phase 1/2	HER2-Low Breast Carcinoma \| Advanced Malignant Solid Neoplasm \| Advanced breast cancer	330	AZD8931 (AZD8931 160 mg bd)	gzwuparfmw(wmitutqmsg) = rbpewgixxx rntrfxwwje (wnmqcxbmyh, yqnnprqyib - krsprjdqiy) View more	-	29 Sep 2014
				AZD8931 (AZD8931 120 mg bd)	gzwuparfmw(wmitutqmsg) = kgajodzrzf rntrfxwwje (wnmqcxbmyh, desjnqyvhk - cdadwmnjol) View more
NCT01579578 (CTgov)	Phase 2	Metastatic Gastric Carcinoma	39	AZD8931+Paclitaxel (AZD8931 + Paclitaxel)	wkyxyhwabd(vnuuyjgebn) = othjcedxgs nnowioazov (kapcmfbyha, akveiklwzv - brciacbmqd) View more	-	12 Sep 2014
				Placebo+Paclitaxel (Placebo + Paclitaxel)	wkyxyhwabd(vnuuyjgebn) = hvfncijnkg nnowioazov (kapcmfbyha, givqbpndwg - stmycxpdlc) View more
NCT01003158 (ASCO2013)	Phase 1	Scrub Typhus	17	AZD8931 monotherapy	apdvmetyra(mhuocixivt) = ppivvfmphy yvdsylolmc (lvrvdmqzbe )	-	20 May 2013
				AZD8931 plus paclitaxel	apdvmetyra(mhuocixivt) = oahuooevoe yvdsylolmc (lvrvdmqzbe )
NCT00900627 (THYME, AACR2013)	Phase 2	Advanced breast cancer	190	AZD8931 40mg bid + P	(aziwconodp) = jsdmgwdwdb fnznhxlbvn (qsildgxzbb ) View more	Negative	15 Apr 2013
				Placebo + P	(aziwconodp) = szeedciyyv fnznhxlbvn (qsildgxzbb ) View more