A NEW approach to prostate cancer treatment, tested in mice, increases the visibility of cancer cells that have spread to bone, giving hope for future new treatments.
Up to 90% of men with treatment-resistant prostate cancer develop metastases in their bones, from which most of these men will die.
The research, led by scientists at Peter MacCallum Cancer Centre in collaboration with Garvan Institute of Medical Research, LaTrobe University and the University of Melbourne, found that reprogramming cancer cells to re-express a protein that made them visible to immune cells could block the growth of cancers in bone and establish immune memory should the cancer ever return.
While some treatments enhance quality of life and delay the onset of skeletal symptoms in men with bone metastases, they have failed to increase survival.
"The key to this approach is to increase immune cell recognition of prostate cancer cells in bone and, importantly, arm the immune system to recognise these cancer cells should they come out of hiding and re-emerge in the future," said Peter Mac's A/Prof Belinda Parker, who is the senior author on the study.
"It is estimated that in over half of men diagnosed with prostate cancer, cancer cells can be found silently residing in their bones in a sleep-like state known as dormancy.
"Dormancy, in which tumour cell division is restricted for up to 20 years from initial local diagnosis, could help to explain the delay in the development of overt bone metastases observed in some men with prostate cancer. Yet, how and why some dormant prostate cancers cells wake up to trigger cancer growth within bones is poorly understood."
Using state-of-the-art single cell sequencing technology at the Garvan Institute, the researchers discovered that the processes allowing dormant cancer cells to awaken and grow also made them invisible to the immune system.
'By looking at the differences between dormant and dividing cancer cells isolated from the bones of mice with prostate cancer, we discovered that, as prostate cancer cells awaken, they switch off their production of an important immune-stimulating pathway - namely the type I interferon (IFN) pathway,' explains Dr Katie Owen from Peter Mac, who led the study.
'It is a double-whammy - not only do the cancers start growing again but their lack of IFN production means that the cancer cells are simply not seen by immune cells,' she said.
The researchers were able to confirm that actively growing bone metastases in men with prostate cancer also had reduced IFN production and were prompted to look for ways to reactivate IFN production in the actively dividing cancers.
"We were particularly interested in a class of drug called HDAC inhibitors as we know that they can modulate the expression of a number of genes inside cancer cells, and some are already approved for use in humans for treating some blood cancers."
When researchers treated mice bearing metastatic prostate cancer cells with a selective HDAC inhibitor, Entinostat, they found that they could achieve re-expression of IFN inside the cancer cells, decrease the outgrowth of bone metastases, and extend survival.
Significantly, the treatment also triggered the activation of specific tumour-killing T immune cells and, when combined with an immune-activator, they were able to completely eliminate bone metastasis. The combination also reduced the activity of certain cells within the bone that can cause bone breakdown.
Future research will confirm whether use of agents that turn on IFN signalling in prostate cancer cells, including HDAC inhibitors, can be harnessed to offer new therapeutic opportunities in men with no current treatment options to combat bone metastasis through immune signalling restoration at the tumour cell level.'
The research was published in the journal EMBO Reports.