BAY 1082439 / Bayer - LARVOL DELTA

A multi-functional nano-system combining PI3K-110α/β inhibitor overcomes P-glycoprotein mediated MDR and improves anti-cancer efficiency. (PubMed, Cancer Lett) - "In our study, a tumor targeting drug delivery nano-system PBDF was established, which comprised doxorubicin (DOX) and BAY-1082439 respectively encapsulated by biodegradable PLGA-SH nanoparticles (NPs) that were grafted to gold nanorods (Au NRs) modified with FA-PEG-SH, to enhance the efficacy to reverse P-gp mediated MDR and to target tumor cells, further, to enhance the efficiency to inhibit MDR tumors overexpressing P-gp. In-vivo experiments further demonstrated that PBDF NPs improved the anti-tumor ability of DOX and inhibited development of KB-C2 tumors. Notably, the metastasis of KB-C2 cells in livers and lungs of nude mice were inhibited by treatment with PBDF NPs, which showed no obvious in-vitro or in-vivo toxicity."

Journal • Oncology • ABCB1 • PIK3CA

Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment. (PubMed, Nat Commun) - "Here we find that intermittent but not daily dosing of a PI3Kα/β/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8 T cell-dependent anti-tumor immunity in vivo...Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT."

IO biomarker • Journal • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Prostate Cancer • Solid Tumor • CD8 • CXCL10 • IFNA1 • IFNG • PIK3CA • PTEN

Pulsatile inhibition of PI3K converts immune suppression by Tregs and M2-TAM to anti-tumor immune response in animal models insensitive or resistant to the monotherapies of PI3K and checkpoint inhibitors (AACR 2018) - "We first compared an oral pan-PI3K inhibitor BAY 1082439 dosed continuously (QD) versus intermittently (2On/5Off), and performed a comprehensive evaluation of an approved intravenously dosed pan-PI3K inhibitor copanlisib (2On/5Off). Taken together, pulsatile pan-PI3K inhibition could effectively convert an immune suppressive effect observed with continuous treatment to a favorable anti-tumor immune response. Combination of intermittently dosed PI3K inhibitor copanlisib with ICIs therefore might be a promising strategy to overcome the resistance induced by intratumoral oncogenic signaling and an immune suppressive tumor microenvironment."

Checkpoint inhibition • Preclinical • Colorectal Cancer

Combination of PI3K inhibitor BAY 1082439 with radium-223 is a promising treatment of cancer with bone metastases (AACR 2014) - Presentation time: Tuesday, Apr 08, 2014, 1:00 PM - 5:00 PM; Abstract #4022; "...BAY 1082439 strongly inhibited tumor-induced osteolysis measured by radiography and led to 53.2% (p=0.16) and 84% (p=0.00698) reduction in total osteolytic area as single agent and in combination with radium-223, respectively. The frequency of soft tissue metastases was also decreased by treatment with BAY 1082439 alone...."

Preclinical • Oncology

Open Label Study of BAY1082439 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=92; Recruiting; Sponsor: Bayer; Trial primary completion date: Jun 2016 ->Apr 2017

Trial primary completion date • Biosimilar • Oncology

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer. (PubMed, Mol Cancer) - "The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges."

Journal

Loss of Dnmt3a Dysregulates Hematopoietic Homeostasis and Myeloid Skewing Via the PI3Kinase Pathway: PI3Kα/β Inhibition Corrects Extramedullary Hematopoiesis and Myeloid Skewing Due to Loss of Dnmt3a (ASH 2019) - "We investigated the role of PI3Kinase signaling in Dnmt3a loss induced myeloid malignancy using pharmacological inhibitor, GDC0941 (PI3Kα/δ inhibitor) and BAY1082439 (PI3Kα/β inhibitor). These results demonstrate that Dnmt3a ablation induces liver specific expansion of hematopoietic cells, and extramedullary hematopoiesis in spleen via aberrant activation of PI3Kinase signaling in HSCPs. Consistent with this notion, PI3K inhibitor treatment of malignant Dnmt3a-/- bearing mice showed significantly improved overall survival compared to controls."

DNMT3A

Co-Targeting the Cell Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ inhibitor BAY1082439. (PubMed, Mol Cancer Ther) - "The anti-PI3Kδ property of BAY1082439 further blocks B cell infiltration and lymphotoxin release, which are tumor microenvironment factors that promote castration-resistant growth. Together, our data suggest a new approach for the treatment of prostate cancer by targeting both tumor cells and tumor microenvironment with PI3Kα/β/δ inhibitor."

Journal