WP2 – Ex vivo high-throughput Drug screening
Rationale
Most current targeted therapies are designed to target tumour cells with a specific genetic alteration. However, many tumours do not carry these “drug matched” genetic alterations.
Furthermore, even with a gene-drug match, far from all tumours respond to the targeted therapy and this has historically been a major challenge in developing new therapies for GBM. To get a better understanding of which drugs and drug combinations may selectively target individual and subgroups of GBMs and how that relates to the comprehensive molecular profiling in WP1, we will perform high-throughput drug screening of ex vivo primary GBM cultures to establish drug vulnerabilities of each tested patient sample.
Objectives
Discoveries of novel therapeutic options in GBM. Stratifying response to current approved and investigational GBM treatments. Guiding discovery of novel predictive molecular biomarkers.
Approach
Primary patient-derived organoid (PDO) cultures from WP4 will be plated in 384-well plates where they will be exposed to physiologically relevant dose response series of drugs and drug combinations using laboratory automation systems available at BRIC.
The drug collection will consist of up to 400 clinically relevant drugs and drug candidates and their combinations as well as experimental agents relevant to molecular profiling data (Figure 4).
Importantly, the collection will be continuously modified based on discoveries in other WPs. A minimum of 20 samples will be profiled each year.
Overall viability and cell subtype drug responses will be assessed by high throughput microscopy to identify individualized drug response “fingerprints” of each patient sample and a phenotypic stratification across the tested cohort.
The cell subtype drug response analysis will allow us to identify drugs that target different phenotypic subpopulations, including GSCs.
Drug responses will be compared to molecular profiling as well as clinical outcomes to generate novel hypotheses on links between genetic and epigenetic aberrations, and therapeutic vulnerabilities.
Selective drug responses and novel drug combinations will be followed up in long term ex vivo cultures and animal models in WP4.
Endpoints
An inventory of drug response patterns across a diverse set of GBMs, understanding of drugs that target key GBM subpopulations, including GSCs.
Expected impact
We will generate novel information on how ex vivo drug responses vary across different GBMs, which will allow for identifying new potentially effective treatment strategies, including how to overcome resistance to existing and emerging therapies. Combining the in vitro drug response information combined with molecular profiling and clinical information, hypotheses on how treatment strategies can be stratified based on molecular biomarkers.