A5056917101- Computational Drug Discovery Methods
- Cancer Immunotherapy and Biomarkers
- Gene expression and cancer classification
- Cancer Treatment and Pharmacology
- Bioinformatics and Genomic Networks
- Gene Regulatory Network Analysis
- Statistical Methods in Clinical Trials
- Cancer Cells and Metastasis
- Gaussian Processes and Bayesian Inference
- Cancer therapeutics and mechanisms
- HER2/EGFR in Cancer Research
- Breast Cancer Treatment Studies
- Ovarian cancer diagnosis and treatment
- Colorectal Cancer Treatments and Studies
- Telomeres, Telomerase, and Senescence
- Bayesian Methods and Mixture Models
- Pharmacogenetics and Drug Metabolism
- Immunotherapy and Immune Responses
- Statistical Methods and Bayesian Inference
- Prostate Cancer Treatment and Research
- Advanced Breast Cancer Therapies
- Glioma Diagnosis and Treatment
- Pancreatic and Hepatic Oncology Research
- PI3K/AKT/mTOR signaling in cancer
- Single-cell and spatial transcriptomics
The Netherlands Cancer Institute
2016-2025
Oncode Institute
2015-2025
Dutch Cancer Society
2019-2023
Utrecht University
2022-2023
Slotervaartziekenhuis
2006-2017
Cancer Genomics Centre
2016
Maastricht University
2012-2013
Cellular senescence is characterized as a stable proliferation arrest that can be triggered by multiple stresses. Most knowledge about senescent cells obtained from studies in primary cells. However, features may different cancer cells, since the pathways are involved induction often deregulated cancer. We report here comprehensive analysis of transcriptome and senolytic responses panel 13 cell lines rendered two distinct compounds. show response to agents composition senescence-associated...
Abstract Tumor-infiltrating lymphocytes (TILs) have been associated with outcomes in HER2-positive breast cancer patients treated neoadjuvant chemotherapy and trastuzumab. However, it remains unclear if TILs could be a prognostic and/or predictive biomarker the context of dual HER2-targeting treatment. In this study, we evaluated association between pathological response (pCR) invasive-disease free survival (IDFS) 389 stage II-III HER2 positive who received anthracycline-containing or...
Over 90% of pancreatic cancers present mutations in KRAS, one the most common oncogenic drivers overall. Currently, KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on combined inhibition SHP2, upstream using allosteric inhibitor RMC-4550 and ERK, LY3214996. This combination shows synergistic anti-cancer activity vitro, superior disruption MAPK pathway, increased apoptosis induction...
To investigate factors contributing to drug side effects, we systematically examine relationships between 4,199 effects associated with 996 drugs and their 647 human protein targets. We find that it is the number of essential targets, not total determines corresponding drugs. Furthermore, within context a three-dimensional interaction network atomic-resolution interfaces, causing more are also characterized by high degree betweenness targets highly shared interfaces on these Our findings...
While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian (HGSOC) remains limited. Some patients, however, achieve lasting responses, emphasizing the need to understand how tumor microenvironment and molecular characteristics influence ICI response. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated stage IV HGSOC who were scheduled for 6 cycles of carboplatin-paclitaxel interval cytoreductive surgery....
To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) patients advanced cancer. Seven were enrolled randomly assigned to receive (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by (Taxol®) 8 (group I) or vice versa II). Patients received as 3-h infusion 15. The median (range) area under plasma concentration–time curve was 2.06 (1.15–3.47) μg h ml−1 1.97...
Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To overtreatment, we need distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) correlates with transition iIBC.Patients were derived a Dutch population-based cohort of 10,090 women pure median follow-up time 12 years. Density, composition and proximity closest cell CD20+...
Although ductal carcinoma in situ (DCIS) is a non-obligate precursor to ipsilateral invasive breast cancer (iIBC), most DCIS lesions remain indolent. Hence, overdiagnosis and overtreatment of major concern. There an urgent need for prognostic markers that can distinguish harmless from potentially hazardous DCIS. We hypothesised features the adipose tissue may be associated with risk subsequent iIBC. performed case-control study nested population-based cohort, consisting 2658 women diagnosed...
Abstract Cancer cell lines differ greatly in their sensitivity to anticancer drugs as a result of different oncogenic drivers and drug resistance mechanisms operating each line. Although many these have been discovered, it remains challenge understand how they interact render an individual line sensitive or resistant particular drug. To better this variability, we profiled panel 30 breast cancer the absence for mutations, copy number aberrations, mRNA, protein expression phosphorylation,...
HER2-driven breast cancer is correlated with poor prognosis, especially during its later stages. Numerous studies have shown the importance of integrin α3β1 initiation and progression cancer; however, role in this disease complex often opposite different stages types tumors. In study, we aim to elucidate a genetically engineered mouse model mammary tumorigenesis. To investigate tumorigenesis vivo, generated MMTV-cNeu targeted deletion Itga3 (Itga3 KO mice). We further used several...
Computational models in biology are characterized by a large degree of uncertainty. This uncertainty can be analyzed with Bayesian statistics, however, the sampling algorithms that frequently used for calculating statistical estimates computationally demanding, and each algorithm has unique advantages disadvantages. It is typically unclear, before starting an analysis, which will perform well on given computational model.
Discovering biomarkers of drug response and finding powerful combinations can support the reuse previously abandoned cancer drugs in clinic. Indisulam is an that acts as a molecular glue, inducing degradation splicing factor RBM39 through interaction with CRL4 DCAF15 . Here, we performed genetic compound screens to uncover factors mediating indisulam sensitivity resistance. First, dropout CRISPR screen identified SRPK1 loss synthetic lethal be exploited therapeutically by inhibitor SPHINX31....
Despite major improvements in treatment of HER2-positive metastatic breast cancer (MBC), only few patients achieve complete remission and remain progression free for a prolonged time. The tumor immune microenvironment plays an important role the response to could contain valuable prognostic information. Detailed information on cancer-immune cell interactions MBC is however still lacking. By characterizing with MBC, we aimed get better understanding why overall survival (OS) differs so widely...
Abstract Motivation Computational models in biology are frequently underdetermined, due to limits our capacity measure biological systems. In particular, mechanistic often contain parameters whose values not constrained by a single type of measurement. It may be possible achieve better model determination combining the information contained different types measurements. Bayesian statistics provides convenient framework for this, allowing quantification reduction uncertainty with each...
An important feature of Bayesian statistics is the opportunity to do sequential inference: posterior distribution obtained after seeing a dataset can be used as prior for second inference. However, when Monte Carlo sampling methods are inference, we only have set samples from distribution. To then either evaluate at these locations and reweight accordingly, or estimate functional description probability use that Here, investigated what extent obtain an accurate joint two datasets if...
Extracellular-matrix features distinguish between long-term versus shorter-term survivors with OligoMBC.
Abstract An important aspect of cellular signaling networks is the existence feedback mechanisms. However, due to complexity networks, as well presence multiple interrelated events, it can be difficult identify which routes are active in any particular context. We have previously shown that Inference Signaling Activity (ISA) a useful method study steady-state oncogenic across different cell lines and inhibitor treatments. ISA did not explicitly include events. Incorporating will increase...
Abstract Microdose studies are exploratory trials to determine early drug pharmacokinetics in humans. In this trial we examined whether the of gemcitabine at a therapeutic dose could be predicted from microdose. prospective, open‐label microdosing study, microdose (100 µg) was given intravenously participants on day 1, followed by (1250 mg/m 2 ) 2. Gemcitabine and its metabolite 2’,2’‐difluorodeoxyuracil (dFdU) were quantified plasma intracellularly using liquid chromatography‐mass...
Cellular senescence is characterized as a stable proliferation arrest that can be triggered by multiple stresses. Most knowledge about senescent cells has been obtained from studies in primary cells. However, features may different cancer cells, since the pathways are involved induction often deregulated cancer. We report here comprehensive analysis of transcriptome and senolytic responses panel 13 cell lines rendered two distinct compounds. show response to agents composition...