Project description
Insight into mechanisms inhibiting inhibition could enhance cancer outcomes
DNA damage occurs continuously as a result of numerous internal and environmental factors. Left unrepaired, this results in mutations within the genomic material, affecting cell or organism survival. PARP1 is an enzyme essential to initiating DNA repair. It is also overexpressed in many cancers (including breast, ovarian and lung cancers), where it likely helps cancer cells survive chemotherapy and radiation therapy. This makes PARP1 inhibitors (PARPi) of interest in the battle against cancer. PARPi have been shown to suppress tumour growth and metastasis but development of resistance to them inhibits efficacy. The EU-funded PARPinhibit project plans to identify proteins modulating PARP1 activity and their roles in resistance to PARP1 inhibitors, with the goal of reducing resistance and enhancing outcomes.
Objective
Inhibition of PARP1 in cancer therapy is a recently adopted strategy to treat cancers where DNA repair is defective, such as breast and ovarian cancer caused by mutations in BRCA1 or BRCA2. In addition, PARP1 inhibitors (PARPi) can be useful even in the absence of BRCA mutations, likely due to pathogenic variants or epigenetic inactivation of other DNA repair related genes. However, development of resistance to PARPi is a significant challenge.
To address this challenge, I propose to identify proteins that modulate PARP1 activity that could be used as additional therapeutic targets. The strength of this project is based on a systems biology overall strategy exploiting multiple independent datasets to identify candidates protein interactors, followed by a rigorous biochemical and genetic approach to characterize this interaction.
Analysis of identified proteins and their role in PARPi resistance will be achieved at three main levels: a) in-silico and molecular studies of the interaction; b) influence on PARP1 activity and role in PARPi resistance after CRISPR-cas9 editing; c) expression levels in breast and ovarian cancer tissues.
Results from this project will illuminate mechanisms of PARPi resistance and generate potential targets for therapy in breast and ovarian cancer. These results will contribute to the reduction in mortality due to breast and ovarian cancer and they will give an answer to this world-wide diffuse challenge.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- social sciencessociologydemographymortality
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
00185 Roma
Italy