Research > Focus A > Work Packages A08

Personalized glioblastoma treatment guided by patient-derived tumor organoids

Summary

This project leverages recently established human glioblastoma organoid models to lay the groundwork for future molecularly stratified studies. We will integrate patient-derived organoids to drug screening pipelines to complement druggable target prioritization from molecular profiling. Using single-cell genomics, we will longitudinally map the clonal evolution of treatment-sensitive and resistant organoids to dissect the genetic and transcriptional mechanisms of resistance.

Task 1

Personalized treatment optimization based on drug sensitivity tests using IPTOs

Steps / Workflow

Predictive preclinical test of possible treatment options derived from molecular profiling of patient tumors
Drug testing in IPTOs
Long-term goal: submission of results for tumor molecular board discussion

Task 2

Harnessing IPTO models to tackle therapeutic resistance

Steps / Workflow

Longitudinal map of clonal evolution: resistant clones selected or appearing upon treatment?
Alterations and complex rearrangements in resistant clones for all treatment arms: competitive advantages for clonal fitness?
Transcriptional programs and cell states driving resistance
Pathways activated in resistant clones as candidate targets

Task 3

Validation of candidate targets to overcome treatment resistance

Steps / Workflow

Validations and functional assays in IPTOs to block transcriptional regulatory machinery leading to resistance
Response of IPTOs quantified by luciferase imaging
IPTO tissue collected: histological analysis of cellular and molecular effects of target inactivation (e.g. on proliferation, apoptosis, senescence, invasion)
Drugs that demonstrate positive response selected for possible clinical evaluation