A5088400718- Pancreatic and Hepatic Oncology Research
- Phagocytosis and Immune Regulation
- Cancer Research and Treatments
- Cancer Immunotherapy and Biomarkers
- Growth Hormone and Insulin-like Growth Factors
- CAR-T cell therapy research
- Immune cells in cancer
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Cancer Cells and Metastasis
- Cancer, Hypoxia, and Metabolism
- Estrogen and related hormone effects
- Immunotherapy and Immune Responses
- Adenosine and Purinergic Signaling
- Cell Adhesion Molecules Research
- Glycosylation and Glycoproteins Research
- Prostate Cancer Treatment and Research
- Radiopharmaceutical Chemistry and Applications
- RNA Interference and Gene Delivery
- Galectins and Cancer Biology
- FOXO transcription factor regulation
- Cancer, Lipids, and Metabolism
- Lung Cancer Research Studies
- Melanoma and MAPK Pathways
- Micro and Nano Robotics
Boehringer Ingelheim (United States)
2021-2025
University of Basel
2019-2023
University Hospital of Basel
2016-2023
Laboratoire d’immunologie intégrative du cancer
2019
Hospital Base
2019
Massachusetts General Hospital
2019
Harvard University
2019
Queensland University of Technology
2011-2018
UNSW Sydney
2013
The University of Sydney
2013
Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but majority experiences limited benefit, supporting need for new therapeutic approaches. Up-regulation sialic acid–containing glycans, termed hypersialylation, is a common feature cancer-associated glycosylation, driving disease progression and immune escape through engagement Siglec receptors on tumor-infiltrating cells. Here, we show that tumor sialylation correlates distinct states reduced...
The propensity of cancer cells to transition between epithelial and mesenchymal phenotypic states via the epithelial–mesenchymal (EMT) program can regulate metastatic processes, progression, treatment resistance. Transcriptional investigations using reversible models EMT, revealed mesenchymal-to-epithelial reverting (MErT) be enriched in clinical samples castrate resistant prostate (mCRPC). From this enrichment, a metastasis-derived gene signature was identified that predicted more rapid...
Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy immune-mediated mechanisms of a novel HER2-targeting ADC bearing potent anthracycline derivate as payload (T-PNU) in human HER2-expressing syngeneic breast cancer model resistant to trastuzumab ado-trastuzumab emtansine. Mechanistically, component induced immunogenic cell death leading exposure secretion danger-associated...
Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin (Ang2/ANGPT2), induces pleiotropic immune mechanisms facilitate tumor rejection in several models. On the one hand, VEGFA/Ang2 blockade induced regression microvasculature while decreasing proportion nonperfused vessels...
T cell–directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen clinical benefit immunotherapies. Here, we demonstrate that therapeutic targeting interferon-γ (IFN-γ)–interleukin-12 (IL-12) pathway relies on ability a population natural killer (NK) cells with tissue-resident traits orchestrate an antitumor microenvironment. In particular, used engineered adenoviral platform as tool for...
<h3>Background</h3> Cancer cells are known to develop mechanisms circumvent effective anti-tumor immunity. The two ectonucleotidases CD39 and CD73 promising drug targets, as they act in concert convert extracellular immune-stimulating ATP adenosine. is expressed by different immune cell populations well cancer of tumor types supports the escaping recognition destruction. Thus, increasing simultaneously reducing adenosine concentrations can lead <h3>Methods</h3> We designed locked nucleic...
Highlights•Microtubule destabilization in dendritic cells drives DC maturation and T cell activation•GEF-H1 is released from microtubules, leading to its release triggers the RhoA-JNK-c-Jun signaling axis AP-1 transcriptional response•GEF-H1 critical for maturation, antigen cross-presentation, anti-tumor immunitySummaryDendritic (DC) activation a step responses. Certain chemotherapeutics can influence function. Here we demonstrate that chemotherapy capable of microtubule has direct effects...
Background The costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery agonist to the tumor side needed eliciting antitumor efficacy while avoiding systemic toxicity. Methods We analyzed immunostimulatory properties a...
Abstract Purpose: PD-(L)1–blocking antibodies have clinical activity in metastatic non–small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms primary resistance may allow prediction response identification new targetable pathways. Experimental Design: Peripheral blood mononuclear cells were collected from 35 with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels,...
Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver improve anti-tumor responses. We recently demonstrated that a distinct microtubule-targeting drug, plinabulin—a clinical-stage novel agent—modulates dendritic cell maturation and enhances immunity. Here, we investigated the effects of plinabulin on macrophage polarization in vitro vivo . Plinabulin monotherapy induced significant growth inhibition mice bearing subcutaneous...
KRAS inhibitors have demonstrated exciting preclinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on tumor microenvironment using a library KrasG12D, p53-mutant, murine pancreatic ductal adenocarcinoma-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term efficacy. Our findings show that SOS1 MEK (SOS1i+MEKi) suppressed growth in syngeneic models increased intratumoral CD8+ T...
Abstract Fibroblast activating protein (FAP) is an attractive target for therapeutic intervention being mainly expressed in malignant tissues. Previous studies have targeted FAP using a variety of methods yet failed clinics. Here, we utilize FAP-targeted T cell engager (TcE) KPCY tumor models to recapitulate pre-clinical environment. The use FAP- TcE efficiently depleted FAP+ fibroblasts vitro and vivo from tumors. This resulted bystander killing cells growth control vivo. effect was not...
Abstract Recent studies have demonstrated that IGF-I associates with vitronectin (VN) through IGF-binding proteins (IGFBP), which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment, and migration. Because IGFs play important roles transformation progression of breast tumors, we aimed to describe the effects IGF-I:IGFBP:VN complexes on function dissect mechanisms underlying these responses. In this study demonstrate substrate-bound are potent...
Background Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses significant fraction of patients. This lack long-term efficacy may be due poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) programmed cell death ligand 1 (PD-L1), aiming overcome resistance anti-PD-L1 monoclonal therapy....
Abstract Insulin-like growth factor (IGF)-I binds to the ECM protein vitronectin (VN) through IGF binding proteins (IGFBPs) enhance proliferation and migration of skin keratinocytes fibroblasts. Although evidence exists for role individual components complex (IGF-I, IGFBP-3 VN), cellular functions stimulated by these together as a remains un-investigated in melanoma cells. We report here that IGF-I:IGFBP-3:VN trimeric stimulates dose-dependent increase WM35 Sk-MEL28 In 3D Matrigel ™ hydrogel...
Abstract Reliable identification of different melanoma cell lines is important for many aspects research. Common markers used to identify include: S100; HMB-45; and Melan-A. We explore the expression these three in four lines: WM35; WM793; SK-MEL-28; MM127. The examined at both mRNA protein level. Our results show that metastatic line, MM127, cannot be detected using any commonly melanoma-associated markers. This implies it would very difficult this particular line a heterogeneous sample as...
Cancer metastasis is the main contributor to breast cancer fatalities as women with metastatic disease have poorer survival outcomes than localised cancers. There an urgent need develop appropriate prognostic methods stratify patients based on propensities of their cancers metastasise. The insulin-like growth factor (IGF)-I: IGF binding protein (IGFBP):vitronectin complexes been shown stimulate changes in gene expression favouring increased cell and a migratory phenotype. We therefore...
Abstract We provide proof-of-concept evidence for a new class of therapeutics that target growth factor:extracellular matrix (GF:ECM) interactions the management breast cancer. Insulin-like factor-I (IGF-I) forms multiprotein complexes with IGF-binding proteins (IGFBP) and ECM protein vitronectin (VN), stimulates survival, migration invasion cancer cells. For first time we physical IGFBP-3:VN in patient tissues; these were predominantly localized to tumor cell clusters stroma surrounding...
<p>Supplementary Figure 7</p>
<p>SOS1i+MEKi combination treatment suppresses KPCY tumor growth <i>in vivo</i> and alters T cell infiltration in the TME. <b>A,</b> Experiment design of schedule. <b>B,</b> Tumor volume (mm<sup>3</sup>) individual tumors mice for indicated clone. TGI is comparing vehicle with SOS1i+MEKi each clone at day 5. Unpaired Student <i>t</i> test performed SD shown, <i>n</i> = 3–5 per group (*<0.05, **<0.01,...