Synthetic viability of homologous recombination-deficient cancers

Información del proyecto

SYNVIA

Identificador del acuerdo de subvención: 681572

DOI

10.3030/681572

Proyecto cerrado

Fecha de la firma de la CE 13 Abril 2016

Fecha de inicio 1 Julio 2016

Fecha de finalización 30 Junio 2021

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 999 437,50

Aportación de la UE

€ 1 999 437,50

Coordinado por

UNIVERSITAET BERN
Switzerland

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

Período documentado: 2021-01-01 hasta 2021-06-30

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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”).

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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