By Gregory Stoloff
(Editor’s introduction) Please scroll down/click to Gregory Stoloff’s article
‘Statins can slash your risk of dying from cancer by up to 50%’ was the excited claim being made in several papers last week. Long-term statin critic Dr Malcolm Kendrick hit back in an irritated blog a few days later describing the claim as “overblown hype” and “complete rubbish”.
As a devoted fan of Malcolm work, this left me in a quandary. On the one hand I knew his views on statins were backed up by forensic research, on the other hand my story about a pioneering cancer clinic in the Daily Mail last week had claimed that statins could help to treat cancer.
The 50% claim originated in two research papers involving thousands of men and women presented at a big cancer conference in Chicago, which reported on studies tracking cancer incidence in patients who were or weren’t taking statins.
Malcolm’s strenuous objection was that not only were these observational studies – so you could only say there was a correlation not causation – but there was a built in bias – sicker people would be more likely to be on statins. What’s more, evidence from more reliable trials showed that it was people with high cholesterol had a lower risk of cancer.
A game changer in the world of cancer
The cancer clinic I’d written about for the Daily Mail is doing something radical and, it seemed to me, potentially game-changing in the way we treat cancer. The Care Oncology Clinic in Harley is treating cancer patients who have pretty well run out of options with a cocktail of four, old, off patent (and consequently very cheap) drugs, one of which is a statin.
It is the brain child of one-time City wiz kid Gregory Stoloff , who formed his own drug company a decade ago and begun searching the medical literature for off patent drugs that had evidence for effectiveness against cancer. He and his team identified hundreds and winnowed them down to the four in the cocktail. The others were an antibiotic, the diabetes drug metformin and a de-worming pill. (This is not a full account so do read the article and the post on this site that went with it).
There was widespread support for the critiques Malcolm and others had mounted, so had Stoloff got it badly wrong? Or were his critics, however informed about statins and their role in heart disease, simply ignorant about the remarkable impact they could have on cancer? Either way the issue seemed important. The best way to find out was to give him the space to put the case for statins as a cancer killer.
How statins slow cancer’s growth and damage its protective shield.
By Gregory Stoloff
The media reports about statins and cancer largely concentrated on the preventative side – could they cut your risk of cancer as well as of heart disease? I’m not so concerned about that. I think that if you are healthy, the benefits of cancer protection with statins don’t outweigh the risk of diabetes and the other known side-effects.
But if you are at raised risk of cancer from gene variations, or if you had cancer previously, then it might be worth it. You may be able to reduce the side effects by taking the statin considerably less often than the daily dose given against heart disease.
Dr Kendrick and others have strongly criticised the use of observational trials as evidence for statin’s effectiveness on the ground that they are misleading, can’t prove causation and are vulnerable to bias. What he seems to rely on are randomised controlled trials, which is odd as his research has uncovered the many ways these trials can be deliberately manipulated to give very misleading results.
Clinical trials are highly artificial experimental set ups that frequently involve younger and fitter patients than those who will actually get statins in the real world. Observational trials record real world activity but they are only a start. If they do show correlations the next step is to determine the mechanism that might be causing it. This is what has now been done for statins and cancer and it is these mechanisms that are important and not just the cholesterol lowering aspects of statins.
Statins’ three pronged attack on cancer
Statins have an impact on cancer cells via at least three different mechanisms. They attach themselves to pathways or proteins that are important for cancer growth, turning them on or off. One is HMG CoA, familiar as the pathway in the liver that packages up fats and cholesterol but it is also found in cancer cells. Another is PPAR Gamma, proteins that control a lot of cell activity including cell death (apoptosis), which is something cancers block. Finally they indirectly reduce the number of a type of receptor on the surface of cells called GLUT 1 that allows in glucose – the energy source for all cells.
Statins’ ability to slow down the action of HMG CoA has a damaging effect in cancer cells because this is the pathway they use to make the cell walls for all the new daughter cells that being are created at a furious rate. By blocking HMG CoA’s activity, statins slow down the rate at which the cancer multiplies and spreads.
As well as impacting on cancer cells’ supply of building materials, statins are able to reduce the energy available to them. They do this by increasing the levels of HDL production. In cancer cells the HDL increase leads to a reduction in the number of surface receptors – known as GLUT 1 – which pull glucose for energy out of the blood stream. Most cells use GLUT1receptors to do this but cancer cells have significantly more than normal cells and, because they are so much more glucose hungry, they are more sensitive to a reduction in numbers than normal cells. Again growth slows down
The third prong of statins’ attack, which involves turning on PPAR Gamma, delivers a double whammy to cancer. One of a cancer cells’ most important survival mechanisms is the ability to turn off a default program known as “apoptosis” that causes a cell to “commit suicide” when it is damaged or starts behaving erratically. Turning on PPAR Gamma activates apoptosis, and since cancer cells are more sensitive to it than normal cells, the cancer starts dying off.
Making a dent in cancer’s shield
PPAR Gamma also influences some immune cells that surround a cancer known as Tumour Associated Macrophages (TAMs). Surprisingly they aren’t there to attack the cancer but to defend it. Our immune system has the ability to both attack and defend cells and another of the tricks in cancer’s survival kit is being able to turn on this protection. Like cancer cells themselves, TAMs are also much more sensitive than healthy cells to PPAR Gamma’s ability to trigger apoptosis. This starts a process that, via a complex series of steps, ends in the macrophages’ suicide and a reduction in the cancer’s protection.
Interestingly the processes that statins target in cancer cells and in the surrounding TAMs are the same ones targeted by the new immunotherapy drugs that last week were being hailed as a breakthrough in treatment because survival times of some of the patients are considerably longer than usual.
Of course there are plenty of unknowns about the way that statins impact on cancer and if we had a rational system of developing new and effective treatments serious research would be underway to answer them. But the brutal truth is that our current research model is not based on science – this looks promising lets test it – but on profit – this old drug looks promising but unprofitable so we will ignore it.
It was in an attempt to find a way round that blockade that drove me to set up the clinic. Statins certainly have an effect on cancer and we know that they are far less damaging than the existing drugs with their massive price tags. So my idea was to try them on an off-label basis and monitor the results.
I believe that we will soon have good evidence for effectiveness and we already know the risks. But even when we present it I don’t believe that the big companies will pick up on it.
Instead I predict that we will see more small individual clinics springing up the exploit the potential of these older and very cheap drugs.