A5009822261- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- CRISPR and Genetic Engineering
- Chronic Lymphocytic Leukemia Research
- Pluripotent Stem Cells Research
- Single-cell and spatial transcriptomics
- Advanced Breast Cancer Therapies
- Epigenetics and DNA Methylation
- Genetics, Aging, and Longevity in Model Organisms
- Advanced biosensing and bioanalysis techniques
- Genetics and Neurodevelopmental Disorders
- RNA and protein synthesis mechanisms
- RNA Interference and Gene Delivery
- Cancer Genomics and Diagnostics
- Renal and related cancers
- Monoclonal and Polyclonal Antibodies Research
Institute of Molecular Biotechnology
2017-2024
Boehringer Ingelheim (Austria)
2024
Medical University of Vienna
2022
Vienna Biocenter
2017-2022
Abstract Mutations in ERBB2 (encoding HER2) occur 2% to 4% of non–small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective HER2-mutant NSCLC due dose-limiting toxicities or suboptimal potency. We report the discovery zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently selectively blocks HER2, while sparing EGFR, inhibits growth cells dependent on oncogenic...
Ascl1 and Ngn2, closely related proneural transcription factors, are able to convert mouse embryonic stem cells into induced neurons. Despite their similarities, these factors elicit only partially overlapping transcriptional programs, it remains unknown whether converted via distinct mechanisms. Here we show that Ngn2 induce mutually exclusive side populations by binding activating lineage drivers. Furthermore, rapidly dismantles the pluripotency network installs neuronal trophoblast cell...
Pooled genetic screening with CRISPR–Cas9 has enabled genome-wide, high-resolution mapping of genes to phenotypes, but assessing the effect a given perturbation requires evaluation each single guide RNA (sgRNA) in hundreds cells counter stochastic drift and obtain robust results. However, resolution is limited complex, heterogeneous models, such as organoids or tumors transplanted into mice, because achieving sufficient representation impractical scaling. This due bottleneck effects...
<p>PRISM screen raw data.</p>
<div>Abstract<p>Mutations in <i>ERBB2</i> (encoding HER2) occur 2% to 4% of non–small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective HER2-mutant NSCLC due dose-limiting toxicities or suboptimal potency. We report the discovery zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently selectively blocks HER2, while sparing EGFR, inhibits...
<p>High-throughput zongertinib PRISM drug sensitivity screen and biomarker analysis.</p>
<p>High-throughput PRISM drug sensitivity screen in cancer cell lines.</p>
<p>Tempus data analysis results.</p>
<p>In vitro biomarker modulation of (phospho-)protein and mRNA levels post poziotinib or zongertinib treatment.</p>
<p>Graphical NMR spectra of zongertinib and BI-3999</p>
<p>MANO method and results. Sheet 1: Primer sequence for the bar code amplification. 2: next-generation sequencing analysis. 3: Raw data zongertinib (BI 1810631 in table) drug sensitivity assay.</p>
<p>In vivo tumor responses for zongertinib monotherapy or combinations.</p>
<p>Tolerability data for zongertinib in mouse xenotransplantation assays.</p>
<p>Synthesis and in vivo DMPK profile of zongertinib</p>
Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation and the innate immune response. However, expression these interferon-stimulated (ISG) in stem is independent from external stimuli such as viral infection. Here, we show that regulatory factor 1, Irf1, directly controlled by murine formative pluripotency gene network transiently upregulated during transition naive to pluripotency. IRF1 binds regions conserved set ISGs required for...
Abstract ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by range of neurodevelopmental defects including Autism. Though it highly conserved in vertebrates and essential for embryonic development the molecular functions are unclear. We identified its murine homolog ZFP462 screen epigenetic gene silencing mouse stem cells (mESCs). Here, we show safeguards neural lineage specification targeting H3K9-specific histone methyltransferase complex...
Abstract Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation, and thus the innate immunity response. Expression these stimulated (ISG) in stem is independent external stimuli such as viral infection. Here we show that regulatory factor 1, Irf1 , directly controlled by murine formative pluripotency gene network therefore upregulated transition from naive to pluripotency. IRF1 turn binds regions conserved set ISGs required for their...