Delving into the Latest Updates on AZD-8186 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

PI3Kβ inhibitors(Phosphatidylinositol 3 kinase beta inhibitors), PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases

Active Indication

Advanced breast cancerAdvanced Malignant Solid NeoplasmAdvanced Prostate Carcinoma+ [6]

Inactive Indication

Advanced Gastric AdenocarcinomaSquamous non-small cell lung cancer

Originator Organization

AstraZeneca PLC

Active Organization

National Cancer Institute

Inactive Organization

AstraZeneca PLC

Seoul National University Bundang Hospital

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC24H25F2N3O4

InChIKeyLMJFJIDLEAWOQJ-CQSZACIVSA-N

CAS Registry1627494-13-6

AZD8186 is an orally-dosed, selective Phosphatidylinositol 3-kinase (PI3K) β/δ inhibitor that binds to PI3Kβ and PI3Kδ, and inhibits kinase activity and downstream pathways in vitro and in vivo. AZD8186 has shown significant anti-tumor activity in PTEN-deficient preclinical models, including prostate, triple negative breast cancer, squamous lung and germinal center diffuse large B-cell lymphoma models. PTEN deficiency is reported in approximately 20% of patients with gastric cancer and in 35-48% of those with human epidermal growth factor receptor 2(HER2)-positive gastric cancer. To date, there have been no clinical trials with AZD8186 alone or in combination with paclitaxel in advanced gastric cancer. Therefore, it is very important to conduct clinical trials of combination therapy of AZD8186 and paclitaxel in patients with metastatic/recurrent gastric cancer who have failed previous therapy, and to identify the clinical factors and biomarkers that predict effects of the combination therapy.
The purpose of the study is to define the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) of paclitaxel and AZD8186 combination therapy in patients with advanced tumors and to evaluate the efficacy of paclitaxel and AZD8186 combination therapy as a second-line therapy in patients with advanced gastric cancer with PTEN aberrations. This study is divided into Phase 1b and Phase 2.

Start Date14 May 2019

Sponsor / Collaborator

Seoul National University Bundang Hospital

NCT03218826

/ Active, not recruitingPhase 1IIT

A Phase I Study of AZD8186 in Combination With Docetaxel in Patients With PTEN Mutated or PIK3CB Mutated Advanced Solid Tumors, Potentially Amenable to Docetaxel

This phase I trial studies the side effects and best dose of PI3Kbeta inhibitor AZD8186 when given together with docetaxel in treating patients with solid tumors with PTEN or PIK3CB mutations that have spread to other places in the body (metastatic) or cannot be removed by surgery. PI3Kbeta inhibitor AZD8186 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving PI3Kbeta inhibitor AZD8186 and docetaxel may work better in treating patients with solid tumors.

Start Date24 Sep 2018

Sponsor / Collaborator

National Cancer Institute

NCT01884285

/ CompletedPhase 1

A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Anti-tumour Activity of AZD8186 in Patients With Advanced Castration-resistant Prostate Cancer (CRPC), Squamous Non-Small Cell Lung Cancer (sqNSCLC), Triple Negative Breast Cancer (TNBC) and Patients With Known PTEN-deficient/Mutated or PIK3CB Mutated/ Amplified Advanced Solid Malignancies as Monotherapy and in Combination With Abiraterone Acetate or AZD2014

This is a phase I, open-label, multicentre study of AZD8186 administered orally in patients with advanced castrate-resistant prostate cancer (CRPC), squamous non-small cell lung cancer (sqNSCLC), triple negative breast cancer (TNBC) and known PTEN-deficient/mutated or PIK3CB mutated/amplified advanced solid malignancies as monotherapy and in combination with abiraterone acetate or AZD2014.

Start Date09 Jul 2013

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-8186

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100 Translational Medicine associated with AZD-8186

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100 Patents (Medical) associated with AZD-8186

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30

Literatures (Medical) associated with AZD-8186

01 Jul 2024·Translational Cancer Research

Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer

Article

Author: Huang, Wentao ; He, Jun ; Qin, Lei ; Wu, Nuwa ; Yu, Wangjianfei ; Zheng, Wanting ; Tian, Siyun ; Hua, Ruheng

BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane immunoglobulin-superfamily receptor, is expressed primarily on cells such as macrophages and dendritic cells. TREM2 has been shown to be associated with diseases such as neurodegeneration, fatty liver, obesity, and atherosclerosis. Currently, it has become one of the hotspots in oncology research. However, the role of TREM2 in pan-cancer, especially pancreatic cancer, remains unclear.MethodsWe used the Tumor-immune System Interactions Database (TISIDB) to explore TREM2 expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to explore TREM2 expression distribution, Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to explore immune infiltration, cBio Cancer Genomics Portal (cBioPortal) to explore genetic variation, Genomics of Drug Sensitivity in Cancer (GDSC) to explore drug resistance, and Kaplan-Meier plotter database to explore the relationship between TREM2 and prognosis in pancreatic cancer. In addition, we used The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases to explore the relationship between TREM2 and lymph node metastasis. We verified the protein level of TREM2 in pancreatic cancer by Human Protein Atlas (HPA) and western blotting and detected the colocalization of TREM2 with malignant cell markers by multiplex immunohistochemistry (mIHC). Finally, we identified the tumor-promoting role of TREM2 in pancreatic cancer via in vitro experiments, such as cell cycle assays, colony formation assays, and transwell migration and invasion assays.ResultsOur results showed that TREM2 was differentially expressed in various tumors according to different molecular and immune subtypes of pan-cancer. It was found that TREM2 was mainly expressed in monocytes/macrophages. In addition, our study showed that TREM2 expression was closely associated with macrophages in the tumor microenvironment (TME) of pan-cancer. TREM2 was shown to be related to anti-inflammatory and immunosuppressive effects in most cancers. Furthermore, we found that amplification was the main somatic mutation of TREM2 in pan-cancer. Further correlational analysis revealed a significant negative association of TREM2 expression with sensitivity to AZD8186, which is a selective inhibitor of PI3K, but not gemcitabine and paclitaxel. Finally, through the knockdown and overexpression of TREM2, our findings verified that TREM2 on cancer cells promoted the progression of PAAD.ConclusionsIn conclusion, our comprehensive analysis identified that TREM2 expression level was correlated with the TME and the immunosuppressive effects. In particular, our study indicated that TREM2 was involved in the progression of pancreatic cancer.

04 Apr 2024·The Oncologist

Correction to: AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20)

01 Feb 2024·Biomedicine & Pharmacotherapy

β1 integrin mediates unresponsiveness to PI3Kα inhibition for radiochemosensitization of 3D HNSCC models

Article

Author: Borodins, Olegs ; Korovina, Irina ; Cordes, Nils ; Willers, Henning ; Seifert, Michael ; Elser, Marc

Phosphoinositide 3-kinase (PI3K)-α represents a key intracellular signal transducer involved in the regulation of key cell functions such as cell survival and proliferation. Excessive activation of PI3Kα is considered one of the major determinants of cancer therapy resistance. Despite preclinical and clinical evaluation of PI3Kα inhibitors in various tumor entities, including head and neck squamous cell carcinoma (HNSCC), it remains elusive how conventional radiochemotherapy can be enhanced by concurrent PI3K inhibitors and how PI3K deactivation mechanistically exerts its effects. Here, we investigated the radiochemosensitizing potential and adaptation mechanisms of four PI3K inhibitors, Alpelisib, Copanlisib, AZD8186, and Idelalisib in eight HNSCC models grown under physiological, three-dimensional matrix conditions. We demonstrate that Alpelisib, Copanlisib and AZD8186 but not Idelalisib enhance radio- and radiochemosensitivity in the majority of HNSCC cell models (= responders) in a manner independent of PIK3CA mutation status. However, Alpelisib promotes MAPK signaling in non-responders compared to responders without profound impact on Akt, NFκB, TGFβ, JAK/STAT signaling and DNA repair. Bioinformatic analyses identified unique gene mutations associated with extracellular matrix to be more frequent in non-responder cell models than in responders. Finally, we demonstrate that targeting of the cell adhesion molecule β1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel β1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors.

100 Deals associated with AZD-8186

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External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Gastric Adenocarcinoma	Discovery	KR	Seoul National University Bundang Hospital	14 May 2019
Castration-Resistant Prostatic Cancer	Discovery	US	AstraZeneca PLC	09 Jul 2013
Castration-Resistant Prostatic Cancer	Discovery	GB	AstraZeneca PLC	09 Jul 2013
Castration-Resistant Prostatic Cancer	Discovery	ES	AstraZeneca PLC	09 Jul 2013
Castration-Resistant Prostatic Cancer	Discovery	CA	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	GB	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	US	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	CA	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	ES	AstraZeneca PLC	09 Jul 2013
Solid tumor	Discovery	-	AstraZeneca PLC	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03218826 (CTgov)	Phase 1	Metastatic Solid Tumor \| Advanced Malignant Solid Neoplasm \| Triple Negative Breast Cancer \| Castration-Resistant Prostatic Cancer \| Metastatic breast cancer \| Prostate Cancer, Hereditary, 7 \| Unresectable Solid Neoplasm \| Advanced Prostate Carcinoma \| Advanced breast cancer	23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level 1)	uqbtfiurtk(uokogkdktr) = cdtrzrcfoc gumpdmxmfu (ogcwoncufl, ezkqmggsye - qzdzfuaaat) View more	-	21 Sep 2023
NCT03218826 (CTgov)	Phase 1		23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level -1)	ssseohzmab(kjvkicjkho) = bhiyoxeirn sfsfomvvvv (luoeiynglx, tkpmgbxlkc - urnebbmrit) View more	-	21 Sep 2023
NCT01884285 (ESMO2018) Manual	Phase 1/2	Castration-Resistant Prostatic Cancer	52	abiraterone acetate+prednisone+AZD8186	(fnaqgdtudv) = diarrhoea (39%) and nausea (27%) pbmzbsxloq (jlfgttxabb ) View more	Positive	22 Oct 2018
NCT01884285 (ASCO 12017 \| ASCO 22017) Manual	Phase 1	Advanced Malignant Solid Neoplasm	87	AZD-8186	(ojnmqpzihx) = 23 SAEs considered reyllpizmj (ckuicaaxza ) View more	Positive	05 Jun 2017