New ways to treat prostate cancer could be on the horizon after researchers worked out how to reverse the disease’s resistance to treatment in what has been suggested is a “major scientific advance”.
They hope the work will lead to a greater understanding of what causes the disease to resist drugs and how to overcome it, reports The Independent.
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.
The scientists says 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 (ICR) 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 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.
“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 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.
The work has since shown that cells within tumours enter a “sleep state” – senescence – transforming into “hormone factories” that 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.
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.”
The team is now planning to run a clinical trial.
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.
Study details
Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance
Christina Guo, Adam Sharp, Johann de Bono, et al.
Published in Nature on 16 October 2023
Abstract
Inflammation is a hallmark of cancer. In cancer patients, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio (NLR), associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives prostate cancer progression in humans remain unclear. Herein we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients. We show that higher blood NLR reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species including myeloid chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel androgen receptor signaling inhibitor (ARSI) resistance, and if inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with ARSI-resistant mCRPC. This combination was well tolerated without dose-limiting toxicity and decreased circulating neutrophils, reduced intratumor CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration, and imparted durable clinical benefit with biochemical and radiological responses in a subset of mCRPC patients. This study provides the first clinical evidence that senescence-associated myeloid inflammation can fuel mCRPC progression and resistance to AR blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
See more from MedicalBrief archives:
Drug delaying prostate cancer by more than a year gets approval in UK
NICE approves enzalutamide for advanced prostate cancer
MRI scans ‘revolutionise’ prostate cancer diagnosis – UK study