Minimising the risk of therapy-related cancers

Around a fifth of cancer survivors will subsequently develop new independent tumours, many of which are caused by the therapies used to eliminate their original cancer. Chemotherapy and radiotherapy work by inducing DNA damage, preferentially but not exclusively in cancerous cells. Cells respond to this DNA damage by triggering apoptosis, which hopefully eliminates the cancer. Unfortunately, non-cancerous cells can also sustain DNA damage during treatment with chemotherapy or radiotherapy. When these mutated cells survive, they can form subsequent malignancies in people successfully treated for their original cancer.

A recent focus of cancer research has been the development of drugs that directly engage apoptosis pathways, rather than provoking DNA damage to indirectly induce tumour cell death. Some of these new drugs have exhibited robust anti-cancer activity in animal experiments and clinical trials. Because direct apoptosis inducers do not need to damage DNA to kill tumour cells, we hypothesised that they may provoke fewer mutations in surviving cells, so may be less likely than current therapies to cause subsequent cancers.

Encouragingly, we found that anti-cancer agents that target Bcl-2 or IAP proteins failed to provoke mutations in surviving cells, in contrast to chemotherapy drugs that were highly mutagenic. These data provide hope that cancer survivors treated with antagonists of Bcl-2 or IAP proteins would have a lower risk of developing therapy-related cancers than those treated with chemotherapy or radiotherapy. Counter-intuitively, death receptor agonists were highly mutagenic. We are exploring the mechanism underlying this activity and the type of mutations these drugs provoke.