Copanlisib

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D / MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36...

In this study, we explored the potential of novel inhibitors for FYN kinase, a critical target in cancer and neurodegenerative disorders, by integrating advanced cheminformatics, machine learning, and molecular simulation techniques. Our approach involved analyzing key interactions for FYN inhibition using established multi-kinase inhibitors such as Staurosporine, Dasatinib, and Saracatinib. We utilized ECFP4 circular fingerprints and the t-SNE machine learning algorithm to compare molecular similarities between FDA-approved drugs and known clinical trial inhibitors...

IC50 = 11 nM (PI3Kδ); 244 nM (PI3Kα); 424 nM (PI3Kβ), 2,230 nM (PI3Kγ).

OBJECTIVE: This study aimed to assess the budget impact of introducing fixed-duration mosunetuzumab as a treatment option for adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies and to estimate the total cumulative costs per patient in the USA. METHODS: A 3-year budget impact model was developed for a hypothetical 1-million-member cohort enrolled in a mixed commercial/Medicare health plan. Comparators were: axicabtagene ciloleucel, tisagenlecleucel, tazemetostat, rituximab plus lenalidomide, copanlisib, and older therapies (rituximab or obinutuzumab ± chemotherapy)...

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...

UNLABELLED: Extracellular vesicles (EV) have emerged as critical effectors in the cross-talk between cancer and normal cells by transferring intracellular materials between adjacent or distant cells. Previous studies have begun to elucidate how cancer cells, by secreting EVs, adapt normal cells at a metastatic site to facilitate cancer cell metastasis. In this study, we utilized a high-content microscopic screening platform to investigate the mechanisms of EV uptake by primary lung fibroblasts...

Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit-risk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies. Specifically, their unique toxicities may contribute to the high incidences in reported serious and high-grade treatment emergent adverse events (TEAEs), thereby reducing their overall tolerability and potentially limiting their successful use...

Prostate cancer is a frequent malignancy in older men and has a very high 5-year survival rate if diagnosed early. The prognosis is much less promising if the tumor has already spread outside the prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling and initially show good efficacy. However, tumor progression due to AR-dependent and AR-independent mechanisms is often observed after some time, and novel treatment strategies are urgently needed. Dysregulation of the PI3K/AKT/mTOR pathway in advanced prostate cancer and its implication in treatment resistance has been reported...

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The DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single-strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo...

The PI3K pathway is one of the most frequently altered signaling pathways in human cancer. In addition to its function in cancer cells, PI3K plays a complex role in modulating anti-tumor immune responses upon immune checkpoint inhibition (ICI). Here, we evaluated the effects of the pan-Class I PI3K inhibitor copanlisib on different immune cell types in vitro and on tumor growth and immune cell infiltration in syngeneic murine cancer models. Intermittent treatment with copanlisib resulted in a strong in vivo anti-tumor efficacy, increased tumor infiltration of activated T cells and macrophages, and increased CD8+  T cell/regulatory T cell and M1/M2 macrophage ratios...

Phosphatidylinositol 3-kinase delta (PI3Kδ) and gamma (PI3Kγ) are predominantly located in immune and hematopoietic cells. It is well-established that PI3Kδ/γ plays important roles in the immune system and participates in inflammation; hence, it could be a potential target for anti-inflammatory therapy. Currently, several PI3K inhibitors are used clinically to treat cancers with aberrant PI3K signaling; however, their role in treating acute respiratory inflammatory diseases has rarely been explored...

PURPOSE: PTEN loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM...

INTRODUCTION: Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. AREAS COVERED: This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL)...

Since dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is associated with the pathogenesis of cancer, inflammation, and autoimmunity, PI3K has emerged as an attractive target for drug development. Although copanlisib is the first pan-PI3K inhibitor to be approved for clinical use, the precise mechanism by which it acts on PI3K has not been fully elucidated. To reveal the binding mechanisms and structure-activity relationship between PI3K and copanlisib, a comprehensive modeling approach that combines 3D-quantitative structure-activity relationship (3D-QSAR), pharmacophore model, and molecular dynamics (MD) simulation was utilized...

BACKGROUND: Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. METHODS: We examined combination therapies aimed at FLT3+ -AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism...

INTRODUCTION: Serious phosphatidylinositol 3 kinase (PI3K) inhibitor-related pneumonitis has raised clinical concerns, and integrated data for this condition are lacking. METHODS: Randomized controlled trials (RCTs) comparing PI3K inhibitor therapy with control treatments from electronic databases and registrations were searched from inception to 1 April 20231 April 2023seven1 April 2023. The outcomes of our study were the incidence and risk of all-grade and grade ≥ 3 PI3K inhibitor-associated pneumonitis compared with controls...

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials...

PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11 /Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC))...

Merkel cell carcinoma (MCC), a rare but aggressive skin cancer, remains a challenge in the era of precision medicine. Immune checkpoint inhibitors (ICIs), the only approved therapy for advanced MCC, are impeded by high primary and acquired resistance. Hence, we dissect transcriptomic heterogeneity at single-cell resolution in a panel of patient tumors, revealing phenotypic plasticity in a subset of treatment-naive MCC. The tumor cells in a "mesenchymal-like" state are endowed with an inflamed phenotype that portends a better ICI response...