Research > Focus C > Work Packages C01
Summary
This project aims to comprehensively assess the tumor exposure of drugs & biologicals commonly used for the treatment of adult and pediatric glioblastoma in order to preclinically prioritize and de-prioritize drugs & biologicals (and combinations thereof) based on their pharmacological properties and thus suitability for the treatment of patients with brain tumors. We will utilize a large spectrum of methodologies and the UNITE Core Collection of orthotopic preclinical models of different molecular subgroups of glioblastoma (genetic mouse models with an intact immune system and patient-derived xenograft models transplanted into immunodeficient mice). This information will be integrated with molecular information including immune microenvironment, the transportome, imaging information, and response evaluation in the same models. The visual abstract below shows the aims and planned tasks of the work package.
Task 1
Selection of antineoplastic drug candidates on the basis of their in silico and in vitro characteristics
Steps / Workflow
- in silico pre-selection of promising drug candidates against brain tumours
- in vitro permeability screening with growth inhibition assays
- validation of screening results with specific uptake/efflux assays
Task 2
Ultrasensitive quantification of candidate drugs against glioblastoma using validated UPLC-MS/MS and QTOF methods
Steps / Workflow
- FDA/EMA-compliant development of validated assays for quantification of drugs in relevant biological matrices
- quantification of drug exposure at the site of action
- pharmacokinetic analysis of drug candidates
Task 3
In vivo assessment of disposition and effect of promising antineoplastic drug candidates in mice
Steps / Workflow
- in vivo assessment of drug disposition using brain and intratumour microdialysis, plasma, CSF, and tissue samples (blood-brain permeability)
- definition of concentration-effect relationship (tumour response, efficacy, potency, and tolerability)
Task 4
Integrative analysis of the results of tasks 1-3 and development of at least one clinical trial design
Steps / Workflow
- identification of target indication
- allometric scaling
- development of study design and dosing schedule
- preparation of scientific advice by competent authority
PRINCIPLE INVESTIGATORS
PFISTER, STEFAN, PROF. DR. MED.
Director Preclinical Research
Hopp Children ́s Cancer Center Heidelberg, German Cancer Research Center (DKFZ), Division of Pediatric Neurooncology & Heidelberg University Hospital, Dep. of Pediatric Hematology and Oncology, Im Neuenheimer Feld 580 , 69120 Heidelberg
HAEFELI, WALTER EMIL, PROF. DR. MED
Head of Department
Heidelberg University Hospital, Dept. of Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany