AZD8835 / AstraZeneca - LARVOL DELTA

Synergistic activity of PI3K inhibitor in combination with AZD6738, ATR inhibitor in breast cancer preclinical model via DNA damage response pathway (SABCS 2022) - "Here, to enhance the efficacy of PI3K inhibitors, we investigated the novel approach combining PI3K inhibitors (alpelisib, AZD8835, AZD8186, NVP-BKM120) with DDR blockade using ATR inhibitor (AZD6738) in breast cancer preclinical models. The combined inhibition of PI3K and ATR showed a synergistic anticancer effect in vitro and in vivo. ATR inhibitor in combination with PI3K inhibitor merits further clinical investigation to enhance the activity of PI3K inhibitor for the treatment of PIK3CA mutated breast cancer patients."

Combination therapy • Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CHEK1 • PIK3CA

Trial in progress: A phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor in patients with relapsed or refractory B-cell non-hodgkin lymphoma (CAPITAL) (AACR 2022) - P2 | "In the JVM2 mantle cell lymphoma (MCL) cell line, capivasertib showed superior activity vs PI3Ka/d (AZD8835) and PI3Kb/d (AZD8186) inhibitors. A total of 272 pts are planned across 28 sites in 7 countries globally (US, Europe, and Asia). Recruitment began in October 2021."

Clinical • IO biomarker • P2 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CD19 • PTEN • TP53

Suppressing the PI3K/AKT Pathway by miR-30d-5p Mimic Sensitizes Ovarian Cancer Cells to Cell Death Induced by High-Dose Estrogen. (PubMed, Biomedicines) - "MiR-30d-5p or AZD8835 sensitized PEO1 cells to tamoxifen. We suggest that miR-30d-5p might be a promising candidate in the therapy of ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • ER • MIR30A • MIR30D • MIR30E • SOX4

Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells. (PubMed, Molecules) - "In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway."

Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • PIK3CA • PIK3CG

Transcriptional Reprogramming of Super-Enhancer Associated Oncogenes Following Inhibition of Cyclin-Dependent Kinase-9 (CDK9) in Aggressive Non-Hodgkin Lymphoma (NHL) (ASH 2021) - "ChIP-Seq analysis confirmed increased global RNAPII pausing at promoters in cells treated with AZD4573, including at recovery genes...Combination of BET bromodomain inhibitor JQ1 and CDK9i reduced expression of recovery genes including MYC and synergistically restricted proliferation of NHL cells...To investigate recovery genes as targets, we used PIM kinase inhibitors SGI1776 (PIM1) and AZD1208 (pan-PIM)...CDK9i leads to transcriptional reprogramming including the upregulation of a subset of SE-associated oncogenes. Targeting recovery oncogenes may enhance sensitivity to CDK9i."

Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2L1 • BCL6 • BRD4 • CDK9 • CXCR4 • IRF8 • MCL1 • PIM1

AZN terminates multiple oncology pipeline drugs - "Terminations: AZD8835 - Area under investigation: solid tumours; Reason for discontinuation: Safety/efficacy."

Discontinued • Oncology

AZD8835 inhibits osteoclastogenesis and periodontitis-induced alveolar bone loss in rats. (PubMed, J Cell Physiol) - "Meanwhile, histological examination showed fewer osteoclasts in the treatment group. In conclusion, these results indicated that AZD8835 is a promising agent to reduce ABL in CP."

Journal • Preclinical

Stability and preclinical efficacy of patient-derived xenograft (PDX) models in endometrial cancer and uterine sarcoma (SGO 2020) - "PDXs of uterine cancer, established by subrenal capsule implantation, had histopathological and genetic similarity and stability. In addition, this technique is useful in identifying and applying suitable targeted therapies in specific uterine cancer groups."

Stability and preclinical efficacy of patient-derived xenograft (PDX) models in endometrial cancer and uterine sarcoma (SGO 2020) - "PDXs of uterine cancer, established by subrenal capsule implantation, had histopathological and genetic similarity and stability. In addition, this technique is useful in identifying and applying suitable targeted therapies in specific uterine cancer groups."

Stability and preclinical efficacy of patient-derived xenograft (PDX) models in endometrial cancer and uterine sarcoma (SGO 2020) - "PDXs of uterine cancer, established by subrenal capsule implantation, had histopathological and genetic similarity and stability. In addition, this technique is useful in identifying and applying suitable targeted therapies in specific uterine cancer groups."

Stability and preclinical efficacy of patient-derived xenograft (PDX) models in endometrial cancer and uterine sarcoma (SGO 2020) - "PDXs of uterine cancer, established by subrenal capsule implantation, had histopathological and genetic similarity and stability. In addition, this technique is useful in identifying and applying suitable targeted therapies in specific uterine cancer groups."

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment. (PubMed, Front Pharmacol) - "AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473...AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment...AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the KRAS mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer."

Journal • BRCA • BRCA1 • BRCA2 • COL1A1 • EIF4EBP1 • KRAS

PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8 T-cell activity. (PubMed, J Immunother Cancer) - "Together these data reveal novel mechanisms by which PI3Kα/δ inhibitors interact with the immune system and validate the clinical compound AZD8835 as a novel immunoncology drug, independent of effects on tumor cells. These data support further clinical investigation of PI3K pathway inhibitors as immuno-oncology agents."

Journal

Screening of PI3K-Akt-targeting Drugs for Silkworm against Bombyx mori Nucleopolyhedrovirus. (PubMed, Molecules) - "In an attempt to screen antiviral drugs against BmNPV, we summarized the commercial compounds targeting PI3K-Akt and selected the following seven oral drugs for further analyses: afuresertib, AZD8835, AMG319, HS173, AS605240, GDC0941, and BEZ235. Western blotting showed that AMG319 and AZD8835 decreased p-Akt expression after BmNPV infection. These results suggest that AZD8835 has application potential in sericulture."

Journal