Preventing cells ‘hijack’ reverses drug resistance in prostate cancer
23 Oct 2023
Advanced prostate cancer tumours can be prevented from hijacking myeloid white blood cells to help fuel their growth, re-sensitising the disease for treatment, suggests new research published in Nature.
Early clinical trial research offered proof for the first time in a human trial that targeting 'feeder' myeloid white blood cells used by tumours could reverse drug resistance and slow tumour progression.
Research led by The Institute of Cancer Research, London, The Royal Marsden NHS Foundation Trust, and The Institute of Oncology Research (IOR) in Switzerland, was funded by Prostate Cancer UK, Cancer Research UK, the Swiss Card Onco grant organisation, the Prostate Cancer Foundation, AstraZeneca, Wellcome and MIHR Biomedical Research Centre supported the Experimental Cancer Medicines Centres (ECMC) Network.
The scientists tested the experimental drug AZD5069, which prevents myeloid cell recruitment to tumours, together with hormone therapy enzalutamide, on 48 patients with advanced disease.
Nearly a quarter (24 per cent) of patients' tumours shrunk by over 30 per cent in response to the combination. There were also notable decreases in circulating levels of prostate-specific antigen (PSA), a marker secreted by the prostate and often elevated by cancer.
Blood levels of myeloid cells also dropped in patients who received treatment, and biopsies following treatment also revealed fewer myeloid cells within their tumours.
The research was prompted by the unexpected discovery that patients with aggressive and resistant prostate cancer had much higher levels of myeloid RNA in their blood.
The team identified that myeloid cells within tumours enter a state of senescence and become ‘hormone factories’ manufacturing signals which support tumour growth, division and survival, and emit signals to the bone marrow to recruit more myeloid cells to enter the tumour and the cycle continues.
The study is the first to prove that blocking the pathway has anti-tumour implications in humans with prostate cancer.
AZD5069 prevents myeloid cells being recruited to tumours by blocking a receptor on myeloid cells called CXCR2, which acts as a conduit’ for recruitment messages sent by myeloid cells already residing in tumours.
Dr Matthew Hobbs, Director of Research at Prostate Cancer UK, which part-funded the research commented: “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 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."