This site is intended for UK healthcare professionals
Medscape UK Univadis Logo
Medscape UK Univadis Logo

Early Trial Reverses Drug Resistance in Prostate Cancer by Targeting 'Hijacked' White Blood Cells

New treatments for prostate cancer could be developed after researchers demonstrated how the disease's resistance to treatment might be reversed in some patients by stopping tumours 'hijacking' myeloid white blood cells to help fuel their growth.

Prostate cancer is the most common cancer in men, with more than 52,000 men diagnosed with the disease every year in the UK — 144 men every day — and more than 12,000 men die every year due to the disease. 

Inflammation is a "hallmark of cancer", said the authors of a new study, who said that in cancer patients, peripheral blood myeloid expansion - indicated by a high neutrophil-to-lymphocyte ratio - was associated with shorter survival and treatment resistance across malignancies and therapeutic modalities. However, "whether myeloid inflammation actually drives prostate cancer progression in humans remains unclear," they pointed out.

Now, in an early clinical trial, researchers led by the Institute of Cancer Research in London, the Royal Marsden NHS Foundation Trust, and the Institute of Oncology Research in Switzerland, have shown that blocking the messages cancer uses to hijack white blood cells can "re-sensitise a subset of advanced prostate cancers" to treatment – shrinking tumours or halting their growth.

The "major scientific advance" followed a decade of work into understanding how myeloid cells fuelled treatment resistance, which had begun with the "surprising" observation that patients with aggressive and resistant prostate cancer had much higher levels of myeloid RNA in their blood. 

New Treatment "Re-sensitises" Advanced Prostate Cancers to Treatment

To determine whether myeloid cells fuelled androgen receptor signalling inhibitor (ARSI) resistance, and if inhibiting a myeloid cell receptor called CXCR2 to block myeloid cell chemotaxis reversed this, the researchers conducted an investigator-initiated, proof-of-mechanism and proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in 48 patients with ARSI-resistant metastatic castration-resistant prostate cancer (mCRPC).

The experimental drug AZD5069 prevented myeloid cells being recruited to tumours by blocking their CXCR2 receptors, which act as a "mailbox for recruitment messages" sent by myeloid cells already residing in tumours. These messages encourage myeloid cells to travel towards places of inflammation, such as tumours, and infiltrate them, explained the authors.

In around one in four (24%) patients, the researchers found evidence that the tumours responded to therapy. 

In response to the drug combination, tumours shrunk by over 30%, dramatic decreases in circulating levels of prostate specific antigen (PSA) were noted, or blood levels of circulating tumour cells dropped.

"Blood levels of myeloid cells also dropped in patients who received treatment, and biopsies following treatment also revealed fewer myeloid cells within their tumours," reported the authors.

The new treatment "re-sensitises" advanced prostate cancers to treatment by stopping tumours hijacking myeloid white blood cells and pulling them as "conspirator" cells into tumours to help fuel their growth, they highlighted.

Reversing Drug Resistance and Slowing Tumour Progression

The study, published in Nature, provided fresh insight into what causes treatment resistance in prostate cancer. It provided the first proof in a human trial that targeting 'feeder' myeloid white blood cells, which are co-opted by tumours to help fuel cancer growth, progression, and resistance to treatment, could reverse drug resistance and slow tumour progression.

The authors added that they also believed this was the first clinical trial to show that CXCR2 blockade reduced myeloid chemotaxis into human mCRPC and could reverse ARSI resistance, imparting "durable" clinical benefit.

Study leader Johann de Bono, professor in experimental cancer medicine at the Institute of Cancer Research and consultant medical oncologist at the Royal Marsden NHS Foundation Trust, said that the "tremendously exciting" research proved for the first time that targeting myeloid cells rather than the cancer cells themselves could "shrink tumours and benefit patients", and that the findings suggested an entirely new way to treat prostate cancer.

The findings were "fantastic", hailed Professor Kristian Helin, chief executive of the Institute of Cancer Research, who said they helped to act as a proof of principle for "disrupting cancer's supportive ecosystem, as a smart new way of targeting tumours".

The study had provided evidence that myeloid inflammation fuelled therapy resistance and tumour growth, and suggested that myeloid targeting warranted evaluation in larger prostate cancer cohorts and in earlier disease stages, said the authors.

"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 de Bono suggested.

Dr Matthew Hobbs, director of research at Prostate Cancer UK, called for pharmaceutical companies to work with researchers to develop new drugs based on the findings, and to test them in larger trials, "turning research into reality".

For more news, follow Medscape on  Facebook, Twitter, Instagram, and YouTube