AZD8186 / AstraZeneca - LARVOL DELTA

Identification of disulfidptosis in esophageal squamous cell carcinoma based on single-cell and bulk RNA-seq data to predict prognosis and treatment response. (PubMed, Front Immunol) - "Drug screening suggested AZD8186 and JQ1 as potential therapies for high-score patients. This study provides a new prognostic signature for ESCC, explores new therapeutic targets, and provides new theoretical support for personalized treatment."

Biomarker • IO biomarker • Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

A novel bone metastasis-related gene signature for predicting prognosis, anti-androgen resistance, and drug choice in prostate cancer. (PubMed, J Bone Oncol) - "Additionally, BMRPS was associated with anti-androgen resistance, and AZD8186 was identified as a potential BMRPS-related drug that holds promise for personalized treatment in PCa. BMRPS facilitates the prediction of prognosis and resistance to anti-androgens in PCa. It also offers insights into the molecular mechanisms of bone metastasis and aids in drug selection for the treatment of PCa."

Gene Signature • IO biomarker • Journal • Genito-urinary Cancer • Infectious Disease • Oncology • Prostate Cancer • Solid Tumor

Molecular mechanisms and therapeutic targets in glioblastoma multiforme: network and single-cell analyses. (PubMed, Sci Rep) - "Drug sensitivity analyses using data from the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) identified potential targeted therapies for GBM, including SB-505,124, staurosporine, and AZD8186. This integrative study underscores the critical roles of the ECM and synaptic remodeling in GBM and suggests novel therapeutic targets to improve personalized treatment strategies for GBM patients."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • COL1A1 • COL4A1

Use of metabolic imaging to monitor heterogeneity of tumour response following therapeutic mTORC1/2 pathway inhibition. (PubMed, Dis Model Mech) - "An integrated multi-modal imaging workflow was developed to assess the heterogeneity of AZD2014 (mTORC1/2 inhibitor) response in a PTEN-null renal cancer model...Increasing PI3K-AKT inhibition by combining with AZD8186 (PI3Kβ inhibitor) further decreased the control-like metabolic signature, showing PI3K-dependent resistance. This demonstrates that MSI-based workflows yield novel insights into the pharmacodynamic effects of mTORC1/2 inhibition in tumours, which classical biomarkers do not resolve. Coupling these workflows with spatial-omics approaches can deliver greater insights into heterogeneity of treatment response."

Heterogeneity • Journal • Kidney Cancer • Oncology • Solid Tumor • PIK3CB • PTEN • SLC2A1

Prognostic feature based on androgen-responsive genes in bladder cancer and screening for potential targeted drugs. (PubMed, BioData Min) - "ARGs played an important role in the progression, immune infiltration, and prognosis of BLCA. The ARGs model has high accuracy in predicting the prognosis of BLCA patients and provides more effective medication guidelines."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CDK6 • PTK2B • TPD52

PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery (clinicaltrials.gov) - P1 | N=23 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2024 ➔ Oct 2025

Combination therapy • Metastases • Surgery • Trial completion date • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PIK3CB • PTEN

Tumor adaptation to PI3K inhibition and its stability increases as a function of time and is overcome by combined inhibiting Bcl2 family proteins (EORTC-NCI-AACR 2024) - "Materials &Methods; Cell culture with cell lines BT474, SKbR3, MCF7 and breast PDXs, drug treatment with PI3K inhibitors BYL-719 (1uM) and AZD8186 (250nM), bulk RNA sequencing. Conclusions; The data suggests that induction of adaptive resistance is in part responsible for the continued persistence of tumor masses after the initial response to targeted therapy but also makes them more sensitive towards Mcl1/Bcl2 inhibitors due to upregulation of an anti-apoptotic program. This can be exploited in a pulsatile combination treatment strategy to circumvent chronic adaptive resistance and improve therapeutic outcomes in patients."

IO biomarker • Oncology • BCL2 • HER-2 • JUN • MYC • PIK3CA

Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer. (PubMed, Transl Cancer Res) - "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. In 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."

Journal • Atherosclerosis • Cardiovascular • CNS Disorders • Dyslipidemia • Gastrointestinal Cancer • Genetic Disorders • Hepatology • Obesity • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • TREM2

Dissecting gastric cancer heterogeneity and exploring therapeutic strategies using bulk and single-cell transcriptomic analysis and experimental validation of tumor microenvironment and metabolic interplay. (PubMed, Front Pharmacol) - "Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets."

Biomarker • Heterogeneity • IO biomarker • Journal • Tumor microenvironment • Gastric Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor • CD36 • KYNU • MSI • SCARB1

Proffered Paper: PI3Kβ acts with mTORC1 to control DRP1 phosphorylation and mitochondrial dynamics in pancreatic cancer (EACR 2024) - "Monotherapy using the clinically-tested PI3Kβ inhibitor AZD8186 to treat in situ pancreatic tumours significantly prolonged mice survival upon cancer diagnosis. PI3Kβ inactivation altered tumour immune cell infiltration.Conclusion In conclusion, PI3Kβ activity contributes to cancer progression by preventing cytotoxic mitochondrial fission and controlling infiltration of immune cells in the pancreatic tumours."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PDX1 • PIK3CB

Dual inhibition of MEK and PI3Kβ/δ-a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer. (PubMed, Front Pharmacol) - " Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kβ/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted."

Journal • Metastases • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • PIK3CB • PTEN

Identification of ZIC2 as a Potential Biomarker Linked with the Clinical Progression and Immune Infiltration of Oral Cancer: A Multicenter Study. (PubMed, Int J Genomics) - "Oral cancer patients with higher ZIC2 expression showed higher drug sensitivity to two compounds including AZD8186 and ERK_2240. We demonstrated the upregulation of ZIC2 in oral cancer and its promoting effect on the clinical advancement of oral cancer. The potential clinical value of ZIC2 in oral cancer deserves attention."

Biomarker • Clinical • Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • CD8 • MIR1322 • ZIC2

β1 integrin mediates unresponsiveness to PI3Kα inhibition for radiochemosensitization of 3D HNSCC models. (PubMed, Biomed Pharmacother) - "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. 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."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA

Dual inhibition of MEK and PI3Kβ/δ–a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer (Front Pharmacol) - "Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity."

Preclinical • Prostate Cancer

Molecular prognostic of nine parthanatos death-related genes in glioma, particularly in COL8A1 identification. (PubMed, J Neurochem) - "Low-score glioma patients were sensitive to AZD3759_1915, AZD5582_1617, AZD8186_1918, Dasatinib_1079, and Temozolomide_1375, while high-score patients were less sensitive to these drugs. Silencing COL8A1 inhibited the malignant characterization. Temozolomide and AZD3759 inhibited COL8A1 expression and cell viability and promoted apoptosis and parthanatos gene expression, which is a target to improve glioma."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CD58 • COL8A1 • FABP5 • SFRP2 • TNFAIP6 • TNFRSF11B • TNFRSF1B

Dual inhibition of MEK and PI3Kβ/δ -A potential therapeutic strategy in PTENwild-type docetaxel-resistant metastatic prostate cancer (Front Pharmacol) - "Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTENwt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity."

Preclinical • Prostate Cancer

PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery (clinicaltrials.gov) - P1 | N=23 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2024 ➔ Sep 2024

Combination therapy • Metastases • Surgery • Trial completion date • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PIK3CB • PTEN

Combined inhibition of CDK4/6 and AKT is highly active against the luminal androgen receptor (LAR) subtype of triple negative breast cancer (TNBC) (AACR 2023) - "The purpose of this study was to investigate the most effective combinations of inhibitors of CDK4/6 (palbociclib), AR (enzalutamide), and PI3K-AKT (alpelisib/capivasertib) against preclinical models of LAR TNBC...In MDA-MB-453 cells, palbociclib-induced phosphorylation of AKT substrates was suppressed by treatment with capivasertib but not with alpelisib alone or with the PI3Kβ/δ inhibitor AZD8186, suggesting that the compensatory activation of AKT was due to a mechanism independent of the PI3K isozymes...Further investigation of the mechanisms of adaptive activation of AKT upon blockade of CDK4/6 in TNBC cells are in progress. In sum, addition of an AKT inhibitor, but not PI3K inhibitors, to palbociclib suppressed the rebound activation of AKT following treatment with the CDK4/6i, supporting a testable therapeutic strategy in LAR TNBC with intact Rb."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1S1 • AR • CDK4 • PIK3CA • PIK3CB • RICTOR

AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20). (PubMed, Oncologist) - P1/2 | "Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569."

Combination therapy • Journal • Metastases • P1/2 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PIK3CB • PTEN

PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=58 ➔ 21 | Trial completion date: Apr 2023 ➔ Mar 2024 | Trial primary completion date: Apr 2023 ➔ Jul 2022

Combination therapy • Enrollment change • Metastases • Surgery • Trial completion date • Trial primary completion date • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PIK3CB • PTEN

Identification of Relevant Genomic Signatures and Potential Targets in Gynecologic Malignancies by Whole Genome and Transcriptomic Profiling (USCAP 2023) - "Results Table: Tumor Type Site N High-TMB cases Biomarkers Treatment Select Molecular signature/ phenotype UEC Uterus 27 15 PTEN, MSI-H, KRAS, PIK3CA, ATM, ARID1A, FGFR2, NF1, PTCH1, CDK12 AZD8186, Trametinib, Alpelisib, Olaparib, PLX2853, Evdafitinib, Sonidegib, Cemiplimab HRD (n=1) MMR (n=11) CDK12/ CCNE1 amp (n=3) USC Uterus 7 0 ERBB2, PIK3CA, KRAS, CHEK2, SMARCB1 Pembrolizumab, Alpelisib, Trametinib, Olaparib, Tazematostat HRD (n=1) CDK12/ CCNE1 amp (n=7) LGSO Ovary 2 0 CDKN2A Abemaciclip MMR (n=2) HGSOF Ovary and Tube 13 1 BRCA1, BRCA2, ARID1A, ERBB2, TSC2, ERCC2, CDKN2A, NF1, Olaparib, Niraparib, PLX2853, Pembrolizumab, Everolimus, Cisplatin, Abemaciclip, Trametinib HRD (n=7) CDK12/ CCNE1 amp (n=2) ECOV Ovary 7 0 PIK3CA, KRAS, CDKN2A, PTEN, ARID1A, BRCA2 Alpelisib, Trametinib, Abemaciclip, AZD8186, PLX2853, Olaparib MMR (n=1) MMMT Uterus and Adnexa 9 2 PIK3CA, PTEN, ERBB2, KRAS, ARID1A, RET, Alpelisib, AZD8186, Pembrolizumab, Trametinib, PLX2853, Pralsetinib HRD..."

Tumor mutational burden • Cervical Cancer • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Gynecologic Cancers • Microsatellite Instability • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Sarcoma • Squamous Cell Carcinoma • Uterine Cancer • AKT1 • ARID1A • BRCA1 • BRCA2 • CCNE1 • CDK12 • CDKN2A • CHEK2 • ERCC2 • FANCL • FGFR2 • HER-2 • HRD • KRAS • MSI • NF1 • PIK3CA • PTCH1 • PTEN • RAD51B • SMARCB1 • TMB • TSC1 • TSC2

Integrative Whole Genome and Transcriptome Sequencing Analysis of Advanced Prostate Cancer Unearths Genomic Signatures and Novel Events of Potential Significance (USCAP 2023) - "Results Table: Mutated Genes / Fusions Alteration Treatment N. of Cases Tumor Type CDKN2A Oncogenic mutation CDK inhibitors 2 1 Adenocarcinoma 1 NEPC HRAS Oncogenic mutation Tipifarnib 1 Adenocarcinoma PTEN Oncogenic mutation AZD8186 and GSK2636771 12 7 Adenocarcinoma 4 NEPC 1 Carcinosarcoma MET Amplification Tepotinib, Capmatinib and Crizotinib 1 Adenocarcinoma TMB Tumor Mutational Burden-High Check Point Inhibitors 2 1 Adenocarcinoma 1 NEPC MSI Microsatellite Instability-High Check Point Inhibitors 1 NEPC CDK12 Truncating and Oncogenic mutation Check Point Inhibitors Olaparib 2 1 Adenocarcinoma 1 NEPC FGFR1/ FGFR2 Amplification/ Oncogenic mutation FGFR inhibitors 2 NEPC mTOR Oncogenic mutation Temsirolimus and Everolimus 1 NEPC NF1 Oncogenic mutation Cobimetinib and Trametinib 1 NEPC ALK SLC45A3-ALK ALK inhibitors 1 Adenocarcinoma PIK3CA Oncogenic mutation Alpelisib and Fulvestrant 1 Carcinosarcoma PALB2 Oncogenic mutation PARP inhibitors 1 Adenocarcinoma BRCA2..."

Metastases • Tumor mutational burden • Genito-urinary Cancer • Microsatellite Instability • Oncology • Prostate Cancer • Sarcoma • Solid Tumor • BRCA1 • BRCA2 • CDK12 • CDKN2A • ERG • ETV4 • FGFR1 • FGFR2 • HRAS • HRD • MBD4 • MED1 • MET • MSI • MUTYH • NF1 • PALB2 • PIK3CA • POLD1 • PPM1D • PTEN • RAD51B • SLC45A3 • TMB

PIK3CA and PTEN mutations as drivers of osimertinib resistance in patients with NSCLC (AACR 2022) - "Importantly, our in vitro experiments from multiple cell line models indicated that PIK3CA-mediated resistance to osimertinib could be partially reversed by co-treatment with AKT (capivasertib, AstraZeneca) and PI3K alpha (alpelisib, Novartis) inhibitors; PTEN-mediated resistance could be rescued by co-treatment with capivasertib and PI3K beta (AZD8186, AstraZeneca) inhibitors. Our in vivo analysis show that PIK3CA GOF CRISPR engineered cells displayed diminished response to osimertinib when implanted in mice; importantly, combination with AKT (capivasertib) or PI3K alpha (alpelisib) inhibitors enhanced response on treatment and delayed outgrowth after withdrawal treatment. In addition, we observed that combination treatment with capivasertib induced tumour stasis in a PIK3CA-E454K and two PTENloss PDX models.Altogether our in vitro and in vivo data provide evidence of PIK3CA mutants and PTEN loss-driven mechanisms of resistance to osimertinib and offer possible..."

Clinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • PIK3CA • PIK3CB • PTEN

Synthetic methodologies and SAR of quinazoline derivatives as PI3K inhibitors. (PubMed, Anticancer Agents Med Chem) - "Lapatinib, afatinib, gefitinib, erlotinib, idelalisib and copanlisib are quinazoline-based, FDA-approved PI3K inhibitors, while compounds like NVPBYL719, GDC-0032, AZD8186, AZD-6482, etc. are under different stages of clinical trials. In light of the above-mentioned facts, in the present study, we have reported different synthetic approaches, mechanisms of anticancer action, and structure-activity relationship analysis of reported quinazoline derivatives as PI3K inhibitors to help researchers working in the field in designing better and isoform-selective PI3K inhibitors."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

The characterization of tumor microenvironment infiltration and the construction of predictive index based on cuproptosis-related gene in primary lung adenocarcinoma. (PubMed, Front Oncol) - "Moreover, AZD5363 and AZD8186 were the inhibitors of AKT and PI3K, respectively, and had lower IC50 and AUC in the low-score CSS group than it in the high-score CSS group. Besides, a scoring system based on CRGs can predict the efficacy of targeted drugs and immune response. These findings may improve our understanding of CRGs in LUAD and pave a new path for the assessment of prognosis and the development of more effective targeted therapy and immunotherapy strategies."

Biomarker • IO biomarker • Journal • Tumor microenvironment • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CSMD3 • MUC16 • TP53 • TTN