A5035446064- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Growth Hormone and Insulin-like Growth Factors
- Cancer Research and Treatments
- Prostate Cancer Treatment and Research
- Metabolism, Diabetes, and Cancer
- Pancreatic and Hepatic Oncology Research
- RNA modifications and cancer
- Bone health and treatments
- DNA Repair Mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Cell Image Analysis Techniques
- Mitochondrial Function and Pathology
- Radiopharmaceutical Chemistry and Applications
- Genomics and Chromatin Dynamics
- HIV Research and Treatment
- Cancer Immunotherapy and Biomarkers
- Glioma Diagnosis and Treatment
- RNA Research and Splicing
- Cancer Diagnosis and Treatment
- Cancer Cells and Metastasis
- Cancer therapeutics and mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Metal-Catalyzed Oxygenation Mechanisms
- Cancer-related molecular mechanisms research
Boehringer Ingelheim (Austria)
2011-2024
Boehringer Ingelheim (Germany)
2017
Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that associated with drug resistance many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM fibroblasts contribute to chemoresistance is unclear. In this study, we found directly support cells secreting insulin-like growth factors (IGF) 1 2, activate insulin/IGF receptors on cells. Immunohistochemical analysis biopsies from patients...
Scaffold modification based on Wang's pioneering MDM2–p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one scaffold that are not prone epimerization as observed for the initial spiro[3H-indole-3,3′-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures complex fused ring system ideally suited bind MDM2 protein and interrupt its protein–protein interaction (PPI) with...
Breast cancer remains the leading cause of death in women owing to metastasis and development resistance established therapies. Macrophages are most abundant immune cells breast tumor microenvironment can both inhibit support progression. Thus, gaining a better understanding how macrophages could lead more effective In this study, we find that cancer-associated express high levels insulin-like growth factors 1 2 (IGFs) main source IGFs within primary metastatic tumors. total, 75% patients...
Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response inhibitory drugs, yet its role in nucleus poorly characterized. Here, we investigated significance cancers and cell line models. In prostate cancers, was predominantly membrane localized benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic)...
Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has attracted interest as target for pharmacological intervention in malignant diseases. Here, we describe BI 853520, novel ATP-competitive inhibitor distinguished by high potency and selectivity. In vitro, the compound inhibits FAK autophosphorylation PC-3 prostate carcinoma cells with an IC50 of 1 nmol/L blocks anchorage-independent proliferation EC50 3 nmol/L, whereas grown conventional surface culture are 1000-fold less...
The tumor suppressor TP53 (p53) is frequently mutated, and its downstream effectors inactivated in many cancers, including glioblastoma (GBM). In tumors with wild-type status, p53 function attenuated by alternate mechanisms amplification overexpression of key negative regulator, MDM2. We investigated the efficacy MDM2 inhibitor, BI-907828, GBM patient-derived brain stem cells (BTSCs) different statuses MDM2, vitro orthotopic xenograft models.In growth inhibition on-target BI-907828 were...
Abstract p53 is known as the guardian of genome and one most important tumor-suppressors. It inactivated in tumors, either via tumor protein (TP53) gene mutation or copy number amplification key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to MDM2 disrupt its interaction with restore suppressor activity, thereby promoting cell cycle arrest apoptosis. Previous clinical experience MDM2–p53 protein–protein antagonists (MDM2–p53 antagonists) have demonstrated...
Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, identification selection biomarkers for enrichment potential responders represents a high priority future trials these agents. Several reports described IGF2 expression subset colorectal cancers, focal amplification responsible some cases. We defined novel cut-off value...
Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance relapse; via insulin-like growth factor (IGF) has been implicated in castration-resistant We evaluated the antitumor activity of xentuzumab (IGF ligand-neutralizing antibody), alone combination with enzalutamide, cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, PC-3) using...
Abstract The E3 ligase MDM2 controls the tumor suppressor function of p53, which is encoded by TP53gene. Compounds designed to bind preventing its interaction with p53 restore ability combat pathogenic processes that underly cancer development. It has become clear from early clinical experience thrombocytopenia represents an on-target, dose-limiting toxicity may restrict therapeutic utility first-generation inhibitors. Dosing less frequently, while maintaining efficacious exposure levels,...
Abstract Inhibition of IGF receptor (IGF1R) delays repair radiation-induced DNA double-strand breaks (DSB), prompting us to investigate whether IGF1R influences endogenous damage. Here we demonstrate that inhibition generates lesions protected by 53BP1 bodies, indicating under-replicated DNA. In cancer cells, or depletion delayed replication fork progression accompanied activation ATR–CHK1 signaling and the intra-S-phase checkpoint. This phenotype reflected unanticipated regulation global...
Abstract PTK2/FAK is a widely expressed non-receptor tyrosine kinase located mainly at focal adhesions. Sensing upstream signals from growth factor receptors as well integrins, the enzyme contributes to activation of multiple downstream signaling pathways involved in regulation cell survival, proliferation and motility. PTK2 protein expression elevated many human cancers, dysregulated known mediate anchorage-independent malignant cells. Inhibition activity thus may interfere with tumor...
Abstract MDM2 inhibitors block the interaction between Tumor Protein p53 (TP53) and MDM2, its key negative regulator, represent a new therapeutic concept for cancer therapy. are designed to restore activity in TP53 wild-type tumors. Several currently being evaluated early clinical development with mainly daily dosing regimens. However, recent data suggest myelosuppression as an on-target, dose-limiting toxicity this class of inhibitors. Particularly thrombocytopenia could limit utility Hence...
Abstract MDM2 inhibitors block the interaction between Tumor Protein p53 (TP53) and MDM2, its key negative regulator, represent a new therapeutic concept in cancer therapy. are designed to restore activity TP53 wild-type tumors. Several currently being evaluated early clinical development. While tumor targeting of has been well documented, recent preclinical data with tool compound Nutlin-3 have shown that activation by local, intra-tumoral injections induces anti-tumor immunity (Cancer Res...
We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces stress by downregulating the regulatory subunit RRM2 ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. Aiming to exploit this effect in therapy we performed a compound screen five breast cancer cell lines with IGF neutralising antibody xentuzumab. Inhibitor checkpoint kinase CHK1 was identified as top hit....
ABSTRACT Breast cancer remains the leading cause of death in women due to metastasis and development resistance established therapies. Macrophages are most abundant immune cells breast tumor microenvironment can both inhibit support progression. Thus, gaining a better understanding how macrophages could lead more effective In this study, we find that associated express high levels insulin-like growth factors 1 2 (IGFs) main source IGFs within primary metastatic tumours. 75% patients show...
<div>Abstract<p>Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance relapse; via insulin-like growth factor (IGF) has been implicated in castration-resistant We evaluated the antitumor activity of xentuzumab (IGF ligand–neutralizing antibody), alone combination with enzalutamide, cancer cell lines (VCaP, DuCaP, MDA...
Abstract MDM2 inhibitors block the interaction between Tumor Protein p53 (TP53) and MDM2, its key negative regulator, represent a new therapeutic concept for cancer therapy. are designed to restore activity in TP53 wild-type tumors. Several currently being evaluated early clinical development with mainly daily dosing regimens. However, recent data suggest myelosuppression as an on-target, dose-limiting toxicity this class of inhibitors. Particularly, thrombocytopenia could limit utility...
<div>Abstract<p>p53 is known as the guardian of genome and one most important tumor suppressors. It inactivated in tumors, either via protein p53 (<i>TP53</i>) gene mutation or copy number amplification key negative regulators, e.g., mouse double minute 2 (<i>MDM2</i>). Compounds that bind to MDM2 disrupt its interaction with restore suppressor activity, thereby promoting cell cycle arrest apoptosis. Previous clinical experience MDM2–p53 protein–protein...
<p><i>In vitro</i> activity of brigimadlin in normal cells.</p>
<p>IC50 in mouse cell lines with different TP53 status.</p>
<p>MDM2 mRNA expression, copy number and brigimadlin <i>in vitro</i> activity in MDM2-amplified cell lines versus MDM2 non-amplified lines.</p>
<p>Dose-dependent regulation of p53 target genes in MDM2-amplified and non-amplified solid tumor cell lines with brigimadlin, alrizomadlin, milademetan.</p>