Andrew Tutt, MB, ChB, PhD

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

Impact

In normal cells, DNA damage is recognized and repaired so that they can continue to grow. 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 and reduce PARP inhibitor resistance and to design new ways to treat these drug resistant breast cancers.

Progress Thus Far

In laboratory studies, the team has found that the reactivated BCRF gene results in the production of a protein that is different from the normal protein, making it detectable by the immune system. They have begun to study this in patients by testing blood samples for evidence of an immune response against the tumor. The second line of research will involve isolating tumor cells from patients that develop PARP inhibitor resistance and grow them in the laboratory to study them in detail.

What’s Next

Dr. Tutt and his colleagues are continuing to search for evidence of an anti-tumor response in patient blood and will study how and where these immune cells become activated to target the cancer. They are also continuing to study patient tumors in the laboratory to understand the mechanisms of resistance to PARP inhibitor therapy. These efforts will help to define methods to release the brakes on the immune system so that PARP resistance can be prevented or to develop novel strategies to treat drug resistant tumors.