Project overview Joint Funding
MARRIAGE (Impaired DNA Repair)
Program: MTT Funding Line: UPGRADE Project type: study-related research project Entity: multiple entities Status: completed
Homologous recombination repair (HRR) defects represent a synthetic lethality for treatment with a group of drugs for blocking the repair of DNA damage, the PARP inhibitors. However, causative mutations leading to the DNA repair defect can often not be identified directly, not even in whole genome sequencing (WGS), of a cancer sample. Therefore, the detection of genomic scars, i.e., imprints of the DNA repair defect on the genome of a cancer sample, is a promising strategy to increase sensitivity in the detection of HRR deficiency.
We have developed the TOP-ART score which makes quantification of genomic scars accessible in both WGS and whole exome sequencing (WES). This score has been used for enrichment of patients in an interventional clinical trial using a PARP inhibitor. Direct response to treatment can be observed for the first time. Intermediate evaluation of this trial has ruled out futility. Collection of samples from this trial will enable unprecedented depth of characterization of HRR deficiency, both at drylab and wetlab levels; the latter in particular via establishment of ex vivo patient-derived cultures and their use for drug sensitivity screening as well as functional assays of HRR deficiency.
Involved Partnersites
Dresden, Frankfurt/Mainz, HeidelbergCoordinators
Dr. Claudia Ball
Dr. Dr. Daniel Hübschmann
Prof. Dr. Hanno Glimm
Head of Department Translational Medical Oncology, NCT Dresden