Clear cell renal cell carcinomas (ccRCC) are partly responsive to immune checkpoint inhibitor therapies that are based on inhibition of PD-1 and CTLA-4. We have described an autochthonous mouse model of ccRCC that is resistant to immune checkpoint inhibitor therapies and have identified numerous candidate immunosuppressive molecular pathways in ccRCC cells and in infiltrating myeloid lineage...
Our immune system possesses an intrinsic capability to recognize and eliminate malignant cells. Yet, tumors frequently subvert this defense by reprogramming tumor-infiltrating immune cells, driving immune evasion and contributing to therapy resistance. Single-cell genomics bear great potential to enhance our understanding of these processes by generating detailed molecular maps of immune cell...
We previously demonstrated in preclinical and case reports that hypofractionated radiotherapy (RT) can induce tumor-specific T cells, thereby acting synergistically with immune checkpoint blockade (ICB), both locally and outside the RT field (abscopal effect). In the current funding period, we have (i) tested novel treatment combinations in mice to improve the abscopal effect, particularly T...
Variants of unknown significance represent the biggest challenge for genomics-based precision oncology making high throughput functional genomics essential to characterize them. Aberrantly activated Fibroblast Growth Factor Receptors (FGFRs) frequently drive tumorigenesis across many tumor entities. Approved selective inhibitors (FGFRis) are available. However, it remains largely unknown which...
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer driven primarily by KRAS mutations. The KRASG12C mutation, while rare in PDAC, represents a targetable alteration with the inhibitors Sotorasib and Adagrasib approved for treatment of lung cancer. Early clinical trials show that while monotherapy with these inhibitors can provide initial clinical benefit in PDAC patients, all...
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality, underscoring the urgent need for novel effective therapeutic strategies. Although direct interference with mutant RAS signaling, the omnipresent oncogenic driver in PDAC, is currently revolutionizing targeted cancer therapy, resistance to RAS inhibitors emerges rapidly necessitating rational...
Class-III BRAF mutations are increasingly identified across all tumor entities. They render the kinase inactive and - contrary to what one might expect – can lead to strong upregulation of the MAPK pathway through dimerization and strong allosteric activation of other Raf kinases such as RAF1 (c-RAF). Due to the inactivity of the kinase, selective BRAF inhibitors such as Vemurafenib or...
Glioma cells form synaptic connections with neurons, facilitating tumor progression and therapeutic resistance, yet the microenvironmental drivers of this synaptogenesis remain unclear. To investigate the mechanisms regulating neuron-glioma connectivity, we developed ElectroGenomics, an integrative spatial electrophysiology and transcriptomics approach combining high-density multielectrode...
Introduction: Molecular tumor boards (MTB) stratify personalized targeted treatment for patients with rare and advanced cancers. Treatment response is assessed by CT/MRI, though limited by suboptimal sensitivity and specificity. Circulating tumor DNA (ctDNA) from blood plasma has emerged as a promising biomarker for noninvasive profiling of tumor mutational landscapes and disease...
Spatial proteomics by matrix-assisted laser desorption/ionization (MALDI) imaging enables rapid, label-free peptide analysis directly from tissue sections. However, in situ peptide identification remains a major challenge, limiting the broader utility of this technique. In this study, we present a novel workflow that integrates Trapped Ion Mobility Spectrometry-based Parallel...
Membrane type 1 matrix metalloproteinase (MT1-MMP) is crucial in extracellular matrix degradation, which facilitates cancer progression and metastasis. Previous studies have shown the feasibility of using phage display-derived radiolabelled bicyclic peptides for positron emission tomography (PET) imaging. This study aimed to identify and characterize novel MT1-MMP-binding bicyclic peptides...
The development of immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity, necessitates treatment cessation and limits ICI efficacy. Comparing different first- and second-line irAE treatments, we found that glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition reduced anti-tumor immunity in mice. We compared these...
Natural killer (NK) cells are critical components of the innate immune system, capable of targeting tumor and virus-infected cells. Their function is regulated by a balance of activating and inhibitory receptors. Among these, NKG2A—encoded by the KLRC1 gene—recognizes the non-classical MHC molecule HLA-E on target cells, delivering inhibitory signals that suppress NK cell cytotoxicity and...
Relapse after allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a major obstacle in the treatment of acute myeloid leukemia (AML), often driven by immune escape mechanisms. NRAS mutations, found in ~12% of AML cases, activate RAS-MAPK signaling and are frequently acquired late in disease progression, suggesting a role in immune evasion and post-transplant relapse.
Using a...
Tumor hypoxia and high cell density are a well-documented phenomenon in tumours and are key factors contributing to radioresistance. Consequently, overcoming these factors are a major challenge in modern radiation oncology.
Functional imaging using F-MISO-, FDG-PET-CT and multiparametric MRT provide non-invasive methods for detecting and quantifying tumor hypoxia and cellularity at a...
Introduction: In the field of dual-labelled tracers and fluorescence-guided surgery (FGS), ICG and IRDye800CW have been established as the most commonly used dyes. However, fluorescent dyes have continued to evolve. In order to investigate the suitability of such new dyes for potential clinical application, a library of dyes was conjugated to a PSMA-617-based tracer (DP). The aim was to...
Background
Current diagnostic methods for primary prostate cancer (PCa), such as image-guided biopsies, carry risks and may miss tumor heterogeneity. This has driven interest in non-invasive imaging approaches like multiparametric MRI (mpMRI) and PSMA PET/CT, which capture the full tumor burden. This study integrates radiomic features from imaging with histopathology and proteomics from...
Introduction: Non-small cell lung carcinoma (NSCLC), including adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), is the most common type of lung cancer, with distinct biological signatures. Accurate classification and molecular profiling are crucial for therapeutic guidance. In this study, we employed mass spectrometry (MS)-based proteomics to analyze a large patient cohort and...
