Projektbeschreibung
Die Blockierung der DNA-Reparatur als Auslöser der Immunantwort gegen Tumore
Die DNA-Mismatch-Reparatur (MMR) ist ein konservierter biologischer Signalweg, der entstehende Fehler während der DNA-Replikation erkennt und korrigiert und somit eine zentrale Rolle dabei spielt, die genomische Integrität zu erhalten. Krebsarten mit MMR-Defizienz sprechen interessanterweise gut auf Immuntherapien an und haben eine insgesamt günstige Prognose. Das EU-finanzierte Projekt TARGET sieht den Grund für diese Beobachtung darin, dass solche Krebsarten Mutationen anhäufen, die Neoantigene absondern, welche wiederum die Tumorimmunüberwachung auslösen. Das Konsortium wird prüfen, ob die Blockierung der Mismatch-Reparatur durch Wirkstoffe eine Anti-Tumor-Immunantwort hervorrufen und das Tumorwachstum eindämmen kann. Die Ergebnisse werden wesentliche Erkenntnisse über die Anti-Tumor-Immunantwort liefern und die Grundlage für die Entwicklung einer neuen Klasse von Krebsmedikamenten schaffen.
Ziel
This project will test for the first time the hypothesis that therapeutic inactivation of DNA repair pathways in cancer cells can be exploited for patient benefit by reawakening an anti-tumor immune response.
Genomic instability and molecular heterogeneity, which occur in cancer cells with DNA repair deficiencies, fuel tumour progression and are associated with poor outcome. An exception is represented by Mismatch repair (MMR) deficient cancers as these tumours are exceedingly genetically heterogeneous but show favourable prognosis and remarkable response to immunotherapy.
The molecular basis for the clinical outcome of MMR deficient cancers has long remained a mystery. Only recently it has become apparent that their biological properties are associated with increased levels of mutations, which unleash adaptive immunity and trigger immunosurveillance.
We have reported that when MMR is impaired, cancers cells grow in immune-deficient mice but are unable to do so in immune competent animals. MMR inactivation increased the mutational burden and led to dynamic mutational profiles, resulting in persistent renewal of neoantigens and engagements of antigen-specific T cells.
These data suggest an unprecedented high risk-high gain approach: the pharmacological blockade of proteins involved in DNA-repair as an anticancer therapy. This unconventional strategy builds on the concept that the immune system can identify and selectively target tumor cells carrying DNA alterations.
Using in vitro and in vivo functional assays we will systematically assess whether and how inactivation of DNA repair genes provokes an immune response and restrict cancer growth. Notably, TARGET will discover and develop inhibitors of MMR and other DNA repair proteins that induce tumor immunity.
The identification of DNA repair pathways which, when disabled, reawaken the immune system will provide transformative knowledge and could lead to the development of an entirely new class of anticancer drugs.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
10124 Torino
Italien