Blood cancer tumours have 'Achilles heel'

A drug used to treat breast and cervical cancer can also target a weak point in some blood cancer tumours, researchers in the School of Cancer Sciences have discovered.

Over the past 15 years, Dr Tanja Stankovic and Professor Malcolm Taylor have identified some patients with chronic lymphocytic leukaemia (CLL) have mutations in a gene called ATM (ataxia telangiectasia gene), which are also found in other blood tumours such as mantle cell lymphoma and T-prolymphocytic leukaemia.

These mutations prevent the gene’s normal role in repairing damaged DNA and controlling the fate of damaged cells. CLL patients with mutations in the ATM gene have a worse prognosis as the cancer cells are less susceptible to chemotherapy drugs.

Tanja has investigated whether tumours with an ATM defect may have an ‘Achilles heel’ that makes them susceptible to particular drugs and her laboratory work has identified that olaparib may be one such drug. Olaparib has been used in nearly 1,000 patients with breast and cervical cancer and is safe and well tolerated.

ATM defective tumours are faulty in repairing DNA and olaparib exploits this by inhibiting another DNA repair pathway by inhibiting a protein called PARP. All cells need to be able to repair damaged cells and the combination of olaparib inhibiting one DNA repair pathway and an ATM mutation affecting another DNA repair pathway may be enough to kill a tumour cell in the laboratory.

‘The ATM mutation occurs only in the tumour cells but not the normal cells and so the normal cells are unaffected by olaparib,’ Tanja says.

A national clinical trial is now underway to see if olaparib works in patients with chronic CLL with ATM mutations and relapsed patients with T-prolymphocytic leukaemia and mantle cell lymphoma.

The work is supported by the Leukaemia Lymphoma Research Fund and Astra Zeneca and the principal investigator is Dr Guy Pratt, Senior Lecturer in Haematology in the School of Cancer Sciences and Honorary Consultant Haematologist at Heart of England NHS Foundation Trust.

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