*** [email protected] ***

Ongoing projects: 

ADORE-TRANSVISION (ADORE institute supported, 2025-2027) Transforming non-cell autonomous screening for oncology and neuroscience

Understanding how different cell types interact in complex biological systems is a key aspect of both oncology and brain disease research. For instance, interactions of neurons with glioma cells correlate to poor patient survival5 and we have shown that these cellular interactions progressively increase during tumor progression. Emerging new technologies now allow us to study such interactions much more systematically than ever before and provide unique new opportunities to better understand disease and design new intervention strategies. This project aims to establish this new technology at ADORE using unique assets already developed in our labs, and apply it in a proof-of-concept study to establish (A) new multi-cell type disease modeling and (B) CRISPR screening for new therapeutic targets involved in neuron-tumor and (C) glia-tumor interactions. Once established, future oncology and neuroscience projects in ADORE will benefit equally from this new technology, including standardized array screen formats, automated live cell microscopy and analysis pipelines, and shared CRISPR libraries.

In the last few years, single-cell technologies have revolutionized our understanding of cell diversity. Together with new CRISPR tools, single-cell technologies have identified many specific (autonomous) roles for specific cell types in complex biological systems. However, a fundamental understanding of these complex systems requires new technology to reveal how different cell types interact and how aberrant interactions lead to disease. Understanding these non-autonomous effects is crucial for a deeper understanding of disease mechanisms and a prerequisite for the development of better intervention strategies. In this project, we aim to exploit new single-cell technologies to study non-cell-autonomous effects between different cell types involved in disease processes in oncology and neuroscience. As a proof of concept, we propose to establish (A) new multi-cell type disease modeling that recapitulates relevant interactions between different neuron types (inhibitory and excitatory); and (B) CRISPR-based screening for new therapeutic targets in neuron-tumor interactions that may prevent neuronal synapses promoting brain tumor growth As the first step, we propose array-based screens using customized CRISPR libraries, during the pilot phase of this project, followed by droplet-based genome-wide screens and introduction of additional cell types, CRISPR-based screening of astrocyte-glioma interactions (project C).

AI-IMPACT (Health Holland funded, 2022-2026): Drug discovery of multi-target (polypharmacological) kinase inhibitors Kinase inhibitors as being used in the clinic commonly target multiple kinase proteins. We have shown that high efficacies of  kinase inhibitors in laboratory experiments can be explained by their ability to inhibit multiple target at once (also called poly-pharmacology). To interface multi-target drugs to tumor vulnerabilities, we have generated a target predictor for 100,000 kinase inhibitors. Based on the availability of 3000 drug-kinase structures present in the KLIFS database (www.klifs.vu-compmedchem.nl), we developed a convolutional neural network prediction model to predict the target fingerprint of these kinase inhibitors using 270,000 compound ligand measurements. This prediction model will enable us to match bioactivity (target) fingerprints to personalized (vulnerability) fingerprints and design optimal compounds that can reach the brain. 

THE TOXICITY ATLAS (Health Holland funded, 2022-2026): Balancing therapy efficacy and adverse events of multitarget therapies Therapy combinations with desirable efficacies might not be easily translated for clinical use given the potential toxic effect of drug combinations. Using a bioinformatic approach, we provide a rationale for selecting therapy combinations aimed to provide an optimal balance between efficacy and side effects. This is expected to enable further implementation of personalized combination therapies in the clinic. Our approach, called the toxicology atlas, forms a global representation of different responses of the human body to FDA approved drugs. This representation will guide us to which vulnerabilities such as additive toxicity have to be avoided.

Team

• Olivier Bequignon (postdoctoral fellow)
• Fleur Cornelissen, MSc, MD (PhD student)
• Yoran Broersma, MSc (PhD student)
• Leon van hout, MD in training (PhD student)
• Xiangming Cai, MSc (PhD student)
• Anna Giczewska, MSc (PhD student)
• Ting Wong, MSc (PhD student)

Other Scientific roles

• Lecturer Bioinformatics at Amsterdam University College (VU/UvA)
• Ad hoc reviewer for scientific journals: Bioinformatics, BJC Pharmacology, British Journal of Cancer, Cancer Biology and Therapy, Cancer Cell, Cancer Discovery, Cancer Drug Resistance, Cancer Reports, Cell Reports, Cells, Clinical Cancer Research, CNS Oncology, iScience, Molecular biosystems, Nature communications, Neuro Oncology, Oncogenesis, Oncotarget, Oncotargets and therapy, Science Advances, Scientific reviews
• Ad hoc reviewer of grant proposals: EU-ERC, CRUK, ISF, UKRI, BTC
• AACR Member
• NET4Brain coordinator NL
• Dr. Bart Westerman reports a relationship with Health~Holland that includes: funding grants. Dr. Bart Westerman received a public-private partnership fund from Health Holland on a peer-reviewed projects where Medstone B.V., IOTA Pharmaceuticals Ltd and NTRC Therapeutics B.V. are the private parties and contributors to the project.
• Supervised over 100 student projects and theses

Alumni

• Ravi Narayan, PhD, now Medical Advisor Europe at Genmab
• Cyrillo Brahm, PhD, now MD in residence
• Megan Houweling, PhD, now science director, Medstone/SURUS consultancy
• George Kanev, PhD, now postdoctoral fellow at St. Jude, Memphis
• Asli Kucukosmanoglu, now bioinformatician at Leyden labs (respiratory vaccine development)
• Rogier Dik, Research Staff Scientist, MSc., now medical science liaison at Abbvie