Ovarian cancer drug could be used against other cancers

A drug used to treat ovarian and breast cancers could be used to tackle other cancers with particular genetic defects, including a common kidney cancer, a study published today has shown.

Research by The Institute of Cancer Research, London, UK, and Gustave Roussy, a cancer institute near Paris, France, has found PARP inhibitors can exploit weaknesses in DNA repair in patients whose cancers have PBRM1 gene defects.

PBRM1 mutations are found in about half of all kidney cancer cases, in mesothelioma, and in some lung or bile duct cancers and although the gene defects are common, there are no treatments that target them.

The research team found that treating PBRM1-defective cancer cells with PARP inhibitors, such as rucaparib, olaparib or talazoparib, in the lab had a “synthetic lethal” effect, which resulted in cell death.

Tumour growth was also halted when they used the PARP inhibitor talazoparib in mice with kidney tumours that had genetic defects in PBRM1, they write in the latest Cancer Research journal.

Cells lacking the PBRM1 protein had higher than usual levels of DNA damage, which worsened when the cells were treated with PARP inhibitors, while both PARP and PBRM1 proteins were found to be involved in repairing cancer cells’ DNA.

Cancer cells can survive with either PARP or PBRM1, but they will die if both DNA repair systems are switched off.

Researchers also found that the presence of PBRM1 had an influence on the anti-cancer immune response. Exposing PBRM1-defective cancer cells to PARP inhibitors not only caused additional DNA damage, but also activated the body’s anti-cancer immune response, further contributing to the elimination of cancer cells, and potentially opening opportunities for keeping cancer patients alive for longer.

Professor Chris Lord, study co-lead and professor of cancer genomics at The Institute of Cancer Research, London, said: “These findings are promising and our colleagues in Paris have already begun trials in patients based on this work. We’re hopeful that this could become a brand new genetically targeted approach to treating cancer and could offer hope to patients with various cancer types including a common form of kidney cancer.”

Study co-leader Dr Sophie Postel-Vinay, at Gustave Roussy in Paris, added: “PBRM1 defects occur frequently on several cancer types, and have for long been ignored because we had no technology that allowed to look for them and diagnose them in the clinical practice, until recently. Our findings open novel perspectives for the treatment of these cancers for which there are currently limited treatment options.

“The fact that PARP inhibitors could also activate the immune response is important, as immunotherapies have brought unprecedented benefits in patients with tumour types where PBRM1 is frequently mutated, such as kidney or lung cancer.”

Professor Paul Workman, chief executive at The Institute of Cancer Research, London, said: “The results show the exciting potential of PARP inhibitor drugs to be active in PBRM1 deficient tumours, including kidney cancer, as well as for increasing the immune response against these cancers.”

The research was funded by Cancer Research UK and organisations in France, including the Institut National de la Santé et de la Recherche Médicale and La Ligue Nationale Contre le Cancer (LNCC).

Cancer Research 23 April 2021

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