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Breakthrough reverses prostate cancer’s resistance to treatment

Researchers said their discovery is ‘tremendously exciting’.

New ways to treat prostate cancer could be on the horizon after researchers figured out how to reverse the disease’s resistance to treatment in what has been hailed as a “major scientific advance”.

It is hoped the work will lead to a greater understanding of what causes the disease to resist drugs and how to overcome it.

In an early clinical trial, scientists from a number of organisations used a combination of treatments to block the messages cancer uses to “hijack” white blood cells.

The drugs resensitised a subset of advanced cancer and led to tumours shrinking or not growing any further.

They say the work provides the first proof that targeting “feeder” myeloid white blood cells, used by tumours to fuel cancer growth, can reverse drug resistance and slow the progression of tumours.

The team was led by the Institute of Cancer Research in London, the Royal Marsden NHS Foundation Trust and the Institute of Oncology Research (IOR) in Switzerland.

Johann De Bono, a professor of experimental cancer medicine at the Institute of Cancer Research (ICR) and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, 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.”

For the study, published in Nature, the team recruited patients with advanced prostate cancer which had stopped responding to hormone therapy.

A combination of an experimental drug which prevents myeloid cell recruitment to tumours – AZD5069 – and the hormone therapy enzalutamide was administered.

From a group of 21 patients who could be evaluated, researchers found responses in five (24%).

Either their tumours shrank by more than 30%, they saw dramatic decreases in circulating levels of prostate specific antigen (PSA), a marker secreted by the prostate which is often elevated by cancer, or their blood levels of circulating tumour cells dropped, in response to the combination.

Patients who received the treatment also showed a drop in myeloid cells in the blood and biopsies revealed fewer cells in their tumours.

The study builds on a decade of work by the team, which has been exploring how myeloid cells fuel prostate cancers.

It started after it observed that patients with aggressive and resistant forms of the disease had much higher levels of myeloid RNA in their blood.

Its work has since shown that cells within tumours enter a “sleep state” known as senescence, transforming into “hormone factories” which support the growth of tumours.

They then send signals to the bone marrow to recruit more myeloid cells to enter the tumour and help it survive.

Prof De Bono added: “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.

“Professor Andrea Alimonti at the IOR then demonstrated in laboratory studies that these cells could promote prostate cancer growth, with their inhibition blocking tumour progression.

“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.”

He said the team is now planning to run a clinical trial.

Professor Kristian Helin, chief executive of the ICR, said: “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.”

The study was funded by Prostate Cancer UK, Cancer Research UK, the Swiss Card Onco grant organisation, the Prostate Cancer Foundation, AstraZeneca, Wellcome and the NIHR Biomedical Research Centre at the Royal Marsden and ICR, with support from the Experimental Cancer Medicines Centres Network.

Prostate Cancer UK’s director of research, Dr Matthew Hobbs, said he is “extremely excited” about the findings.

“A man living with advanced prostate cancer needs treatments that will control his disease to give him years more life, feeling as well as possible,” he said.

“Sadly, for many men, their cancer resists treatments, ending too many lives far too soon.

“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.

“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 to 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.”

Publication of the paper comes after it was suggested that making changes to how MRI scans to detect prostate cancer are carried out could lead to faster diagnosis of the disease.

Researchers from University College London (UCL) and University College Hospital said a two-step MRI – without the need for patients to be injected with an iodine-based liquid to help enhance scan images – could be “just as effective”.

A UCL-led study, known as Precision and published in 2018, created a five-point scoring system called Pi-Qual to rate MRI image quality, with five being optimal for diagnosis.

As part of its Glimpse trial, researchers analysed 355 MRI scans from 41 medical centres across 18 countries.

Some 32% had achieved the highest Pi-Qual score of five.

The team contacted each centre and, when 36 from 17 countries resubmitted MRIs, the score rose to 97%.

Glimpse forms part of the Prime trial, which is exploring whether a shorter and cheaper MRI scan could become the new standard of care.

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