We explore the role of a class of chemical compounds called bisphosphonates in treating breast cancer patients.
Today, these drugs are used to treat some breast cancer patients who have developed bone metastasis but new research reported today (7 November 2014) in the press could help repurpose these drugs for the treatment of breast cancer before it has spread.
A (very) brief history
Bisphosphonates were first synthesised by chemists in the late 1800s, originally to be used as chemical agents to soften water by mopping up calcium and magnesium in the water supply. The intriguing chemical properties of bisphosphonates stirred excitement amongst the medical research community in the 1960s and led to a rapid increase in research on the medicinal use of the compounds.
The first big breakthrough came in the late 60s when scientists discovered that bisphosphonates had the ability to stop crystals formed of calcium breaking apart – a key feature of the progressive bone disease called osteoporosis. It wasn’t long before research in the laboratory and in animal models was able to show that this chemical feature of bisphosphonates could indeed prevent the breakdown of bone.
From here the story is characteristic of medical research. Bisphosphonates were trialled successfully in humans for conditions including damage to tissue caused by excess calcium, destructive bone disease such as Paget’s, multiple myeloma and cancers which have spread to the bone (metastasis). But why would these compounds be capable of treating cancer metastasis to the bone?
Cancer cell buffet
One reason the bone may be a common site of metastasis is because the cellular environment within the bone is a veritable buffet of biological molecules that support growth and development of tumours. This makes the bone a favourable place for cancer cells, which once stuck in to a feeding frenzy, begin to cause breakdown of the bone matrix. This releases even more nutrients and growth molecules creating a perpetual cycle promoting tumour growth.
Bisphosphonates can shut this buffet down by taking down the chefs – cells known as osteoclasts. These bone cells help regulate the structure of the bone and play a key role in topping up the plentiful supply of molecules exploited by metastatic cancer cells. Research has now shown that bisphosphonates can stop cancer cells sticking to the bone, prevent bone breakdown and release of growth molecules, and directly kill cancer cells.
Bisphosphonates such as pamidronate, ibandronic acid, sodium clodronate and zoledronic acid are all used to treat breast cancer which has spread to the bone. These drugs have different uses and while some can treat the cancer itself, others are used to treat the symptoms caused by bone metastasis.
Potential new use
New research reported in the press today has provided new evidence to demonstrate how bisphosphonates could be used to treat primary breast cancer. Clinical trials carried out a number of years ago have shown some evidence that these drugs can improve survival when given to primary breast cancer patients but no one had been able to work out why. Using some incredible imaging techniques the researchers were able to see that bisphosphonates stuck to calcium deposits in tumours, which in turn seemed to activate nearby cells of the immune system. The addition of bisphosphonate seemed to ‘wake up’ the immune system and cause the cells to attack and destroy the drug-calcium complexes on the tumour as they would an invading bacterium.
The implications of this are that waking up these cells with bisphosphonates could help the patient’s own immune system to target and remove tumour cells. This research was carried out in mice so we still need to see how these findings translate into humans, but it’s an incredibly exciting area of research which we will be watching with interest.
Dr Matthew Lam is Breakthrough Breast Cancer's Senior Research Officer