Andrew Tutt, MB, ChB, PhD

Seeking to understand the factors associated with PARP inhibitor resistance and improve outcomes for patients with breast cancer.

Impact

In normal cells, DNA damage is recognized and repaired to ensure the genomic integrity of the cell. However, in breast cancer cells with inherited mutations in genes such as BRCA1 or BRCA2, the ability to repair damaged DNA is impaired. This vulnerability in cancer cells has been exploited with treatments, such as PARP inhibitors which block alternative DNA repair processes these tumor cells depend on. Although these drugs are effective, tumor cells can further mutate to restore BRCA function and overcome the lethal effect of the therapy. Dr. Tutt and his team are studying this phenomenon and hope to define steps that can block it, reduce PARP inhibitor resistance, and design new ways to treat these drug-resistant breast cancers.

Progress Thus Far

In laboratory studies, the team has found that the restored BRCA gene produces an abnormal protein that is detectable by the immune system. Similarly, they have seen theprotein in blood from patients. Preliminary findings in patient blood suggest an immune response against tumors with specific [BRCA?] mutations. Studies are ongoing to understand how to harness this to help the immune system fight the resistant tumor. Lastly, Dr. Tutt and others have found that in addition to inherited mutations in BRCA genes, loss of function can also occur through a process called methylation, particularly in triple-negative breast cancers. They have shown that BRCA1 methylation is detectable after surgery and are pursuing another line of research to delve into this finding.

What’s Next

Dr. Tutt and his colleagues are continuing to search for evidence of an anti-tumor response in patient blood with the goal of developing vaccine strategies. They are continuing to study patient tumors in the laboratory to understand the mechanisms of resistance to PARP inhibitor therapy and developing a test for BRCA1 methylation that can be used after chemotherapy and surgery to identify patients who may benefit from PARP inhibitor therapy.