Prostate cancer resistance to treatment can be reversed in some patients by preventing white blood cells from being “attracted” to tumors, according to new research published in Nature.
In an early clinical trial, researchers showed that blocking the messages that cancer uses to take over white blood cells can re-sensitize a subset of advanced prostate cancers to treatment — shrinking tumors or stopping their growth.
The research provides the first evidence in a human trial that targeting “feeder” myeloid white blood cells – which are recruited by tumors to help fuel cancer growth, progression and resistance to treatment – can reverse resistance to drugs and slow tumor progression.
The research, led by Institute of Cancer Research, LondonThe Royal Marsden NHS The Foundation Trust and the Institute for Oncological Research (IOR) in Switzerland represent a major scientific advance after a decade of work to understand how myeloid cells fuel treatment resistance.
The study was funded by Prostate Cancer UK, Cancer Research UK, the Swiss Card Onco grant agency, the Prostate Cancer Foundation, AstraZeneca, Wellcome and NIHR Center for Biomedical Research at the Royal Marsden and the Institute of Cancer Research (ICR)with support from the Network of Experimental Medicines for Cancer Centers (ECMC).
Researchers tested a combination of AZD5069, an experimental drug that prevents the recruitment of myeloid cells to tumors, and enzalutamide, a hormone therapy commonly used to treat prostate cancer, in 48 patients with advanced disease.
Five of the 21 (24 percent) patients had evidence that their tumors were responding to treatment.
This meant their tumors shrunk by more than 30 percent, saw dramatic reductions in circulating levels of prostate-specific antigen (PSA), a marker secreted by the prostate that is often elevated by cancer, or levels of circulating cancer cells in the blood they were reduced. response to the combination.
Levels of myeloid cells in the blood also decreased in treated patients, and post-treatment biopsies also revealed fewer myeloid cells in their tumors.
The research builds on over a decade of work by teams at ICRRoyal Marsden and the IOR are working to understand how myeloid cells fuel prostate cancers.
This began with a surprising observation that patients with aggressive and resistant prostate cancer had much higher levels of myeloid RNA in their blood.
Research by this international team has since shown that myeloid cells within tumors enter a dormant state called ‘senescence’ and become ‘hormone factories’, producing signals that support tumor growth, division and survival. They then send further signals to the bone marrow to recruit more myeloid cells to “conspire” to enter the tumor and the cycle continues.
The new study is the first to show that blocking this pathway has an anti-tumor effect in people with prostate cancer. It is an example of a treatment that works by disrupting the cancer ecosystem – a pioneering approach to cancer treatment that is a key focus of ICRHer latest strategy, Fight Cancer.
AZD5069 treatment prevents the recruitment of myeloid cells to tumors by blocking a receptor on myeloid cells called CXCR2, which acts as a mailbox for recruitment messages sent by myeloid cells already in tumors.
These messages encourage myeloid cells to travel to and infiltrate sites of inflammation, such as tumors.
Study manager Professor Johann De BonoProfessor of Experimental Cancer Medicine at the Institute of Cancer Research, London and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“This research demonstrates for the first time that targeting myeloid cells instead of cancer cells can shrink tumors and benefit patients. This is extremely exciting and suggests that we have a whole new way of treating prostate cancer on the horizon.
“We were studying these myeloid cells in the ICR for many years. More than a decade ago, we first noticed that they were elevated in patients with much more aggressive tumors and showed that these tumors were more resistant to treatment. Professor Andrea Alimontis at the Institute of Oncology Research (IOR) then demonstrated in laboratory studies that these cells could promote the growth of prostate cancer, with their inhibition preventing tumor progression.
“It is very rewarding to see our theory proven in a trial of patients with this disease. Myeloid cells may be involved in resistance to therapy in a range of cancers, so the impact of this research could be very broad, across many types of cancer.”
“It is a significant achievement to design and conduct a clinical trial with mainly philanthropic funding. We are incredibly grateful to charities such as Prostate Cancer UK, Cancer Research UK, the Prostate Cancer Foundation and the grant organization Swiss Card Onco, who made this research possible.’
Professor Kristian Helin The Chief Executive of the Institute of Cancer Research London said:
“It is fantastic to see such an innovative approach to treatment showing benefits in a clinical trial. It helps serve as a proof-of-principle for disrupting cancer’s supportive ecosystem as a smart new way to target tumors.
“I look forward to seeing how this work develops and hope it paves the way for a new treatment that is beneficial for people with prostate cancer, and potentially many other types of cancer.”
Dr Matthew HobbsDirector of Prostate Cancer Research UK, who part-funded the research, commented:
“A man living with advanced prostate cancer needs treatments that will control his disease to give him years more to live, to feel as good as possible. Unfortunately, for many men, their cancer resists treatments, ending too many lives too soon.
“Six years ago, Prostate Cancer UK brought together some of the world’s leading experts in the field to discover how prostate cancer uses 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 an entirely new, safe, effective way to treat advanced, resistance-free prostate cancer.
“I am extremely excited about these results and proud that we are funding such ground-breaking research. Now we want to see drug companies work with researchers to develop new drugs based on what we’ve learned and test them in larger trials – turning research into reality for men.”
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