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New class of precision oncology drug strips cancer of its DNA defences

Damage to the DNA in cells is the root cause of cancer, but it is also a weakness of the disease whereby the cancer cells can be killed by further damaging their DNA or by preventing its ability to repair their DNA.

A new precision medicine that targets the ability of cancer to repair its DNA has shown promising results in the first clinical trials of the drug class. The study was originally designed to test the drug’s safety, but found that half of the patients given the new drug, either alone or with platinum chemotherapy, saw their tumour stop growing. In two patients, their tumours shrank or disappeared completely.

The trial is in phase I and is the first in a new family of drugs that block a key DNA repair protein, ATR. Phase I trials are designed to assess the safety of new treatments.

The team at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, led the trial on the benefit of an ATR inhibitor, Berzosertib, either on its own or with chemotherapy in 40 patients with very advanced tumours. The researchers found the drug is safe for use in further clinical trials, determined the doses at which it was safe to use and when delivered on its own it caused only mild side effects.

It is unusual for a phase I trial to find that the drug had such a response in the patients as it did, with 20 out of 38 patients, whose response could be measured, had their tumours stop growing. The benefit of the drug was even more marked in patients who were given it in combination with chemotherapy. In these patients, 15 of 21, saw their disease stabilise, suggesting the chemotherapy boosted the sensitivity to Berzosertib.

Patient response

The response to the phase I trial has been remarkably good. One patient with advanced bowel cancer, whose tumour contained faults in the CHEK1 and ARID1A genes, responded well to Berzostertib on its own, his tumours disappeared and he has remained cancer-free for more than two years.

Another patient, a woman with advanced ovarian cancer whose disease came back after treatment with a PARP inhibitor received the combination of Berzosertib and chemotherapy and saw her tumours shrink. This indicates that Berzosertib could be explored as a strategy to overcome resistance to PARP inhibitor treatments.

The drug is now moving into further clinical trials with the hope that it could be developed into a targeted treatment for patients and help overcome resistance to other precision medicine drugs.

The results were published yesterday in the Journal of Clinical Oncology and was funded by Merck KGaA, the manufacturer of the drug.

The ICR is focusing on overcoming cancer evolution and drug resistance in its new Centre for Cancer Drug Discovery. Previously, the ICR discovered how to genetically target the first approved precision medicine attacking cancer’s ability to repair DNA, the PARP inhibitor Olaparib.

Professor Johann de Bono, Head of Drug Development at the ICR and The Royal Marsden said the new clinical trial is the first to test the safety of a brand new family of targeted cancer drugs in people, and it’s encouraging to see some clinical responses at this early stage.

He added that in the future, this new class of ART inhibiting drugs could boost the effectiveness of treatments like chemotherapy, expand our range of treatment options and overcome resistance to other targeted treatments.

Professor Paul Workman, Chief Executive of The Institute of Cancer Research London said that “targeting a cancer’s ability to repair its DNA is a fundamentally important avenue of cancer research”, and that is it exciting to see the first clinical trial of a drug targeting a key player in the DNA repair process have such promising results, and that he is keen to explore the potential for ATR inhibitors.

Image credit:  Medical photo created by kjpargeter –