Blocking Oestrogen in Breast Cancer

04 October 2009

Interview with

Professor Charles Coombes, Cancer Research UK, Imperial College

Kat -   In case you haven't noticed, October is breast cancer awareness month across the UK.  You've probably seen the explosion of pink in the shops and I do think it's a real shame that we don't have blue everywhere for men's cancer, so I think there's something to be done there, chaps, come on - get sorted.  Anyway, breast cancer is still the most common cancer in the UK and it affects around 45,000 women and around 300 men every year.  And although survival rates are improving year-on-year, there are thousands of people who still lose their lives to breast cancer.  And often, this is because hormone blocking treatment such as tamoxifen or anastrozole stop working after a while.  Now, Cancer Research UK's Professor Charles Coombes is a leading breast cancer researcher at Imperial College in London.  And I went to find out more about the role of hormones in breast cancer and some of the promising new treatments, he and his team are developing.

EstriolCharles -   Hormones, mainly oestrogen, drive breast cancer cells to divide.  So it acts as a sort of a fertilizer for breast cancer cells and tamoxifen has been the standard way that people try to block oestrogen action because tamoxifen is an anti-oestrogen drug.  So, it prevents oestrogen from gaining access to the cells that cause the cells to divide.  The problem is, that more than half of breast cancers eventually become insensitive to tamoxifen.  And so, the first drug that we developed was - if you want, a drug that would work after tamoxifen has exerted it's action and worked.  And that class of drugs is called aromatase inhibitors.  And those drugs are drugs such as Arimidex, exemestane, letrozole, those sorts of drugs are all inhibitors of oestrogen synthesis.  Under those circumstances, what happens is that a cancer cell becomes resistant to tamoxifen by over expressing the oestrogen receptor and the way to make those cancer cells die is to withdraw oestrogen completely.  If you withdrew oestrogen after tamoxifen treatment, you could get a lot of cancer cells to die that had become resistant to tamoxifen.

Kat -   And that's what these aromatase inhibitors do?

Charles -   Exactly.  So, what we've been trying to understand is why do cancer cells, breast cancer cells, become resistant to aromatase inhibitors?  This has been the next big challenge.  And after about 15 years of work, we now think that we understand the mechanism.  What happens is that various other signalling pathways in the breast cancer cell as it were, impinges on the oestrogen receptor.  So, it increases its sensitivity.  So, this is a hypersensitized oestrogen receptor.  Now, aromatase inhibitors, although they stop the body from making oestrogen, and lower the oestrogen significantly, often by as much as 99%, they don't actually reduce it by 100%.  But this low level of persistent oestrogen can be amplified - the effect of that can be amplified by various other enzymes which can be used to target in breast cancer.  So, one enzyme that we recently discovered that does this is something called CDK-7 and we now, over the last two years have developed a specific inhibitor for CDK-7 which prevents the activation of the oestrogen receptor.  So, that drug is now being optimized and will be - we hope available for women whose cancer cells have become resistant to aromatase inhibitors.  Another route that we have gone down and which has already produced a drug which is now being tested throughout Europe is in looking for other sources of this residual tiny percentage of oestrogen that remains after aromatase inhibitors have been used.  It turns out that breast cancer cells can bypass the aromatase pathway by using a storage form of oestrogen.

Ball-and-stick model of the tamoxifen molecule, as found in the solid state.Kat -   So it's a bit like having a spare tank of oestrogen hidden away.

Charles -   Exactly.  In a storage form called oestrogen sulphate.  And there's an enzyme called oestrogen sulphatase which cleaves the sulphate off, thus liberating the oestrogen.  And so, it's a very clever way that the breast cancer cells use this enzyme to liberate the oestrogen which can then sit on the receptor, even when aromatase inhibitors are being used, and then drive the cancer cells to divide.

Kat -   So, how do you try and combat the actions there?

Charles -   Right.   Well, it's taken again about 15 or 20 years work mainly by chemists, again, Cancer Research UK supported, at Bath University and at Imperial College, have made the first inhibitor of this enzyme.  There hasn't been any inhibitor up to date, but this new drug has now been tested by our group here and has been found to completely abolish the enzyme activity and this is the drug that's in trials, in patients with breast cancer whose cancers have become resistant to aromatase inhibitors.

Kat -   And that was Professor Charles Coombes from Cancer Research UK at Imperial College, talking about the promising role of enzyme inhibitors that alter the activity of oestrogen on breast cancer.

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