New class of precision medicine strips cancer of its DNA defences

These GEITP pages do not usually focus on cancer drug therapy, but this article presents a new approach to the problem of attacking cancer cells. A new precision medicine — targeting the cancer cell’s ability to repair its own DNA — has shown promising results in the first clinical trial of this drug class. The new study, designed to test the drug’s safety, found that half the patients given the new drug — either alone or with platinum chemotherapy — saw their cancer stop growing, and two patients saw their tumors shrink or disappear completely. DNA damage (mutations, genomic instability) in a cell is the root cause for inititation and growth of cancers; however, it is also a fundamental weakness in tumors, and cancer cells can be killed by further damaging their DNA — or attacking their ability to repair it.

The new phase I trial tested the first in a new family of drugs that block a key DNA repair protein called ATR (ATR serine/threonine kinase). Phase I trials are designed to assess the safety of new treatments, and it is unusual to see a clinical response at this early stage. A team at the Institute of Cancer Research (ICR), London, and The Royal Marsden NHS Foundation Trust, led a trial in 40 patients with very advanced tumors, located in hospitals around the world — to test the possible benefit of an ATR inhibitor called berzosertib (M6620), either on its own or in combination with chemotherapy. The researchers established the doses at which the drug was safe for use in further clinical trials, and were pleased to find that berzosertib alone caused only mild side-effects. Surprisingly for a phase I trial, authors [see attached article] team found that berzosertib stopped tumor growth in 20 out of 38 patients whose treatment response could be measured.

The drug’s benefit in blocking DNA repair was even more striking in patients also given a DNA-damaging drug such as carboplatin chemotherapy. In these patients, 15 of 21 (71%) saw their disease stabilize — indicating that chemotherapy had boosted sensitivity to berzosertib. One male with advanced bowel cancer (whose tumor contained defect in key DNA repair genes including CHEK1 and ARID1A) responded remarkably well to berzosertib on its own, seeing his tumors disappear and remaining cancer-free for more than 2 years. One woman with advanced ovarian cancer — whose disease had returned after treatment with a drug that blocks PARP (poly(ADP-ribose) polymerase-1, another key DNA repair protein), received the combination treatment and saw her cancer masses shrink (this patient’s response suggests that berzosertib could be explored as a strategy to overcome resistance to the PARP inhibitor family of targeted treatments).

The drug is now moving forward into Phase II clinical trials, and the hope is that it could be developed into a new targeted treatment for patients, therapy that might help overcome resistance to other precision medicines such as PARP inhibitors that target DNA repair. The trial was funded by Merck KGaA, Darmstadt, Germany, manufacturer of the drug. The Institute of Cancer Research (ICR), a charity and research institute, will be focusing on how to overcome cancer evolution and drug resistance in its new Centre for Cancer Drug Discovery, for which it still needs to raise a final £2 million to complete these clinical trials. Authors concluded that, to their knowledge, this report is the first of its kind for an ATR inhibitor as monotherapy, and, combined with carboplatin. M6620 was still well tolerated, with amazing “target engagement” and preliminary anti-tumor responses observed. 😊



J Clin Oncol Jun 2020; ePub, DOI

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