Monday, 14 October 2013

Losartan - High-Blood Pressure Drug Helps Fight Cancer

We treat cancer with the most vicious, toxic and carcinogenic drugs available to science in the form of chemotherapy. But the fact is that the chemotherapy drugs are brutally effective at killing cells - at least initially, and at least when they can get to the cells we want to target. But, as we all know, most chemotherapy drugs are not easily targeted and end up killing plenty of non-cancerous cells. Not only that, cancer cells are also able to find various methods of shielding themselves from the poisonous brew or they mutate and become resistant. This means that no matter how good chemo drugs are at killing cells, if tumour cells are able to hide or adapt then that killing power is ultimately useless (not to say downright dangerous to the rest of the body). The upshot of this is that finding ways of getting more chemotherapy to more cancer cells is a hugely useful strategy if we can do it.

One mechanism by which cancer cells cells are shielded from chemotherapy (and other treatments, including radiotherapy), is through the decreased blood supply inside solid tumours. As tumours develop they constrict blood vessels into the interior of the tumour, stopping nutrients and oxygen getting to the cells deep inside the mass. With the vessels so constricted it's also the drugs carried in the blood supply - like chemotherapy drugs - which are cut off from the cells at the heart of the tumour. Furthermore, in response to this restrict supply of food and oxygen, the cancer cells adapt and become more aggressive and able to cope with the harsh conditions that surround it. These adapted cells are also more likely to form metastases, spreading the cancer to other parts of the body where conditions are easier, at least initially.

One possible way to stop this is to look at 'tumour vasculature normalisation' as a therapeutic strategic. The idea behind this is that by reducing the constriction of blood vessels into the tumour, then blood, oxygen and blood-borne drugs can make it into the heart of the tumour. In this way there is a reduced push towards more aggressive mutations, reduced risk of metastases and of course a greater delivery of cancer-killing drugs like chemotherapy. It seems counter-intuitive to want to make it easier for tumours to have a blood supply, but sometimes it's the counter-intuitive ideas that work the best in practice.
While there are various drugs being developed to achieve this normalisation of the tumour vasculature, a recent paper in the journal Nature suggests that one commonly used, cheap and safe drug can already do this. Losartan (trade name Cozaar, though it is also available as a lower cost generic drug), is a commonly prescribed anti-hypertension (high blood pressure) drug which seems to have a number of possible uses as a anti-cancer drug.

Firstly, losartan has been shown to target the over-expression of AGTR1 in a subset of breast cancers. This means that treatment with losartan could significantly reduce tumour growth in those breast cancers which fit the molecular profile (which could be in the region of 10 - 20% of breast cancers). This is as good a result as specially developed targeted drugs that have cost millions to develop and for which we don't yet have the safety data compared to something like losartan, which now costs pennies and which has been used for many years.

However, the new results (published as an open access paper here: http://www.nature.com/ncomms/2013/131001/ncomms3516/pdf/ncomms3516.pdf), shows that in breast and pancreatic tumours in mice the combination of losartan and chemotherapy significantly reduced tumour growth rates and had a positive effect in terms of survival. This is a really positive result, and a cliinical trial has started using losartan and existing chemotherapy drugs for the treatment of pancreatic cancer (http://www.clinicaltrials.gov/ct2/show/NCT01821729).

The fact that it's a cheap, commonly available and safe drug that is making the difference is a good news story that is being repeated again and again - from beta blockers to aspirin to statins and metformin, there is a lot of progress being made on repurposing existing drugs for anticancer activity and this is great news.

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