Synthetic viability of homologous recombination-deficient cancers

Projektinformationen

SYNVIA

ID Finanzhilfevereinbarung: 681572

DOI

10.3030/681572

Projekt abgeschlossen

EK-Unterschriftsdatum 13 April 2016

Startdatum 1 Juli 2016

Enddatum 30 Juni 2021

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 999 437,50

EU-Beitrag

€ 1 999 437,50

Koordiniert durch

UNIVERSITAET BERN
Switzerland

Periodic Reporting for period 4 - SYNVIA (Synthetic viability of homologous recombination-deficient cancers)

Berichtszeitraum: 2021-01-01 bis 2021-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Although various effective anti-cancer treatments have become available over the last decades, therapy resistance remains the major cause of death of cancer patients with disseminated tumors. Striking examples are patients with tumors that are defective in the repair of DNA double strand breaks by homologous recombination (HR). Due to this defect, the patients initially show high response rates to DNA damage-inducing cancer therapy. Unfortunately, the development of resistance of primary or disseminated tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. It is therefore crucial to understand the molecular mechanisms underlying this therapy escape in order to impact the current annual cancer mortality of about 2 million people in Europe.
The overall goal of the SYNVIA project is to target the clinical hurdle of anti-cancer therapy resistance. For this purpose, we addressed the problem of therapy escape by using powerful genetically engineered mouse models of breast cancer deficient in the tumor suppressor genes BRCA1- and BRCA2, which closely mimic the human disease. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair. Similar to the situation in cancer patients, we observed that cancer cells in these models eventually escape the deadly effects of chemotherapy or novel targeted drugs. Thus, these resistance models provide a unique opportunity to explore therapy escape mechanisms.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

By synergizing the advantages of next generation sequencing with functional genetic screens in our tractable model systems, we identified novel mechanisms that cause resistance of HR-deficient cancers by the loss of another gene (“synthetic viability”).

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our BRCA1/2 models are not only tools to understand therapy escape mechanisms, but they have also yielded basic knowledge about DNA repair pathways and the mechanism of action of inhibitors of the enzyme poly-ADP ribose polymerase (PARP), which helps damaged cells repair themselves and could be exploited in a targeted therapeutic approach. Moreover, we found that the alterations that render cells resistant to such targeted therapies cause new synthetic dependencies that can be targeted to overcome resistance.

project summary