At least 1/20 women with breast cancer carry a germline BRCA1 variant (mutation). BRCA1 encodes a protein that is critical for homologous recombination DNA repair and breast cancers with germline BRCA1 pathogenic variants are deficient in homologous recombination repair. Fortunately, a new class of cancer therapy that targets the poly(adenosine diphosphate–ribose) polymerase (PARP) family of enzymes exploits the principle of synthetic lethality to selectively kill tumour cells that have a deficiency in homologous recombination repair. Proof-of-concept for clinical activity has been shown in advanced germline BRCA1 pathogenic variant–associated breast, ovarian, prostate, and pancreatic cancers. However, as with most cancer therapies, resistance to PARP inhibition can emerge. New therapies are needed to reduce recurrence in patients with BRCA1 germline mutation–associated early breast cancer.
The student will use CRISPR-Cas9-based gene editing technologies to create a panel of BRCA1-mutant and competent patient cell lines. These are tools that are desperately needed in the field. These matched lines will then be used to: (i) identify mechanisms of PARP inhibitor resistance, and (ii) screen new or combination therapies for their ability to specifically kill BRCA1-deficient cancers. Design, cloning, and implementation of gene editing vectors, fluorescence microscopy, and cell cycle, DNA repair, and viability assays will be applied.
The most important outcome of this project will be a set of research tools that can be used to improve therapy outcomes for cancer patients.