Most women initially respond well to hormonal treatment, which involves drugs such as tamoxifen; these target cancer cells expressing the oestrogen receptor, reducing oestrogen levels or blocking the receptor from working properly.
However, some breast cancer cells – with stem cell-like properties – do not express the oestrogen receptor and can persist and cause relapse. “There is a group of patients who the current treatments fail and who relapse with breast cancer at 5 years but also 10 and 15 years,” said Robert Clarke, from the Institute of Cancer Sciences at the University of Manchester.
Now, Clarke and others have combined tamoxifen with a compound called Sulforadex, from Evgen Pharma. This one-two hits the cancer cells expressing the oestrogen receptor and the cancer stem cells. The research supporting the combination therapy is being reported this week at the American Association of Cancer Research annual conference.
Evgen developed Sulforadex, a patented, synthetic and stabilized version of a common plant compound called sulforaphane. This is a well-known plant chemical found in broccoli, Brussels sprouts and rocket salad, though not in sufficient quantities to reliably treat a tumour. Sulforadex is made in a process that incorporates a stabilizing agent from the outset.
“It is synthesized by our manufacturing partner in North Carolina [Pharm Agra], which makes the active pharmaceutical ingredient. We import this and put it into capsules at a [contract] manufacturing facility here in the UK,” explained David Howat, head of research and development at Evgen Pharma.
“Often the clinical trials are just broccoli extracts with unknown levels of sulforaphane, but our product delivers a precise level of sulphoraphane and is stable for over two years and so is a drugable product.”
Evgen are also looking at Sulforadex as a possible treatment following subarachnoid haemorrhage, a type of stroke.
The cancer cells that survive drugs with tamoxifen seem rely on the Wnt pathway, which is highly active in mammalian development, explained Clarke. Sulforadex specifically targets this pathway.
“We find that resistant cells often have a cancer stem cell phenotype and we know already that the Wnt signaling pathway is very strong in those cancer cells. It just so happens that this compound appears to target the Wnt signaling pathway,” said Clarke.
The combination of drugs will potentially allow for oestrogen-sensitive cells to be targeted, whilst mopping up cells that cause treatment resistance.
Resistance
The new research shows that, in patient-derived cancer cells and tumours from such cells placed in a mouse model, Sulforadex helps overcome resistance by targeting the cancer stem cells.
Sulforadex can be administered as a pill, as is tamoxifen. “There is a little bit of formulation trickery in encapsulating it for slow release in the gut, but essentially it is just dissolved and absorbed,” said Clarke.
“It is not absolutely clear how and why it targets the Wnt signaling pathway in these cancer stem cells. We think it is targeting enzymes involved in epigenetics, which controls whether genes are switched on or off. It may be that by targeting epigenetic enzymes, sulforaphane switches the cancer cells to be less stem-cell like.”