Advanced prostate cancer drug resistance ‘reversed’

Drug resistance in prostate cancer could be reversed by blocking the messages that target white blood cells, according to new research involving British scientists.

The research, published last night, shows that hijacking white blood cells can re-sensitise a subset of advanced prostate cancers to treatment, which results in the tumours shrinking or stopping growing.

Writing in the latest edition of Nature, the research team, led by The Institute of Cancer Research, London, The Royal Marsden NHS Foundation Trust, and The Institute of Oncology Research (IOR) in Switzerland, say it is the first proof in a human trial that targeting ‘feeder’ myeloid white blood cells can reverse drug resistance and slow tumour progression.

They tested a combination of AZD5069, an experimental drug that prevents myeloid cell recruitment to tumours, and enzalutamide, a hormone therapy commonly used to treat prostate cancer, in 48 patients with advanced disease.

Tumours shrunk by more than 30% in five out of 21 (24%) patients and they also saw dramatic decreases in circulating levels of prostate-specific antigen (PSA).

Blood levels of myeloid cells also dropped in patients who received treatment, and biopsies following treatment also showed there were fewer myeloid cells within their tumours.

The new study is the first to prove that blocking this pathway has anti-tumour activity in humans with prostate cancer. It is an example of a treatment that works by disrupting the cancer ecosystem – a pioneering approach to cancer treatment which is a key focus of the ICR’s latest strategy, Defeating Cancer.

The treatment AZD5069 blocks a receptor on CXCR2 myeloid cells, which act as a mailbox for recruitment messages sent by myeloid cells already in tumours. These messages encourage myeloid cells to travel towards places of inflammation, such as tumours, and infiltrate them.

Study leader Professor Johann De Bono, professor in experimental cancer medicine at The Institute of Cancer Research, London, said: “This research proves for the first time that targeting myeloid cells rather than the cancer cells themselves can shrink tumours and benefit patients. This is tremendously exciting, and it suggests we have an entirely new way to treat prostate cancer on the horizon.

“We’ve been studying these myeloid cells at the ICR for many years. More than a decade ago we first noticed that they were elevated in patients with much more aggressive tumours, and showed these tumours were more treatment resistant.

“It’s hugely rewarding to see our theory proven in a trial of patients with this disease. Myeloid cells may be implicated in treatment resistance in a range of cancers, so the impact of this research could be very broad, across multiple cancer types.”

Professor Kristian Helin, chief executive of The Institute of Cancer Research, London, added: “It’s fantastic to see such an innovative approach to treatment showing benefits in a clinical trial. It helps to act as a proof of principle for disrupting cancer’s supportive ecosystem, as a smart new way of targeting tumours.

“I look forward to seeing how this work progresses and hope it will pave the way to a new treatment that is beneficial to people with prostate cancer, and potentially also many other cancer types.”

Dr Matthew Hobbs, director of research at Prostate Cancer UK, which part-funded the research said he was excited by the initial results.

“Six years ago, Prostate Cancer UK brought together some of the world’s top experts in the field to work out how prostate cancer is using the immune system to evade treatments, and how we can disrupt this,” he said.

“Since then, we’ve moved from initial ideas to laboratory research, and now to a clinical trial that shows us a completely new, safe, effective way treat advanced prostate cancer without resistance.

“I’m extremely excited by these results, and proud that we’re funding such revolutionary research. Now we want to see pharmaceutical companies working with researchers to develop new drugs based on what we’ve learnt, and to test them in larger trials — turning research into reality for men.”

Guo C, Sharp A, Gurel B et al. Targeting CXCR2 reduces myeloid inflammation in prostate cancers to reverse therapy resistance. Nature 16 October 2023; doi: 10.1038/s41586-023-06696-z.


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