BSH 2014
Aspirin analogues developed for anti-cancer effects on leukaemia
Dr Chris Pepper - Cardiff University School of Medicine, Cardiff, UK
Basically, as you may or may not be aware, there’s a lot of new drugs for the treatment of CLL so why would you want to develop any new ones, especially when we’re seeing such good activity with some of these novel BCR inhibitors. Well, the answer to that is that, to start with, a lot of these new drugs are incredibly expensive so from a health economics perspective they may not be affordable, certainly in the short term until we get downward pressure on cost. So aspirin and its analogues, lots of companies in that space, but essentially these are relatively simple molecules to make so, potentially at least, could be very cost effective in terms of drugs. If you take aspirin as a good example of that it’s a few pence for an aspirin tablet across the counter.
So that’s why we’re interested in aspirin as a backbone, if you like, for drug entity. Why are we interested in aspirin and its analogues for the treatment of CLL particularly? There’s quite a bit of evidence that aspirin has anti-cancer effects but particularly in leukaemia there was a study that I don’t actually think has been published yet, there was an abstract last year at ASH, which suggested that patients who were on FCR, which is fludarabine cyclophosphamide rituximab which is the gold standard therapy for CLL, actually did better if they were also taking aspirin as part of… nothing to do with their leukaemia, just they were taking aspirin usually because of some underlying coagulation problem or blood thinning strategy. So, yes, it was a fascinating finding so that has piqued our interest in these sorts of drugs.
My interest in aspirin pre-dates that; we’ve been working on these analogues for ten years with a medicinal chemist who is a colleague and friend of mine. We’ve screened probably 250-odd of these analogues over the last ten years. I’m rambling but essentially we’re interested because we think that there’s probably an anti-tumour effect that can be ascertained from the co-administration of aspirin.
The interesting thing about this analogue is that it’s more potent mole for mole. So aspirin itself, to get the anti-cancer effects you’d probably have to be taking a reasonably large dose of aspirin. One of the problems with high dose aspirin is that you get bleeding effects because, as I said to you, you get anti-coagulation effects, it affects an enzyme, the activity of an enzyme, called COX-1 which actually inhibits platelet aggregation. So what we wanted to develop was a novel aspirin analogue that had more potency and more selectivity for the other COX enzyme, COX-2, which does not have this sort of inhibitory effect on platelets.
We’ve only been using it in the context of CLL but also what we’ve done is compare the effects of the agent in CLL cells and in normal B- and T-lymphocytes derived from healthy donors and indeed from patients themselves. So what we want to try and do is make a big therapeutic window. What I mean by that is actually increase the effect on the tumour cell without having an effect on normal tissue, that’s the therapeutic window. Traditionally chemotherapy drugs have a very narrow therapeutic window so their effects also affect normal tissue almost as much, if not more so, than the tumour that they’re trying to target and that has implications for what we can dose at. Obviously if chemotherapy is toxic to normal tissue then that will have very adverse effects on the patient.
Can anyone make this analogue?
We haven’t patented this drug and we haven’t patented it on purpose actually. We wanted it to be open access. Now, there are issues relating to non-patenting of drugs in the sense that which drug company is going to take up a drug that hasn’t got patent protection. But I suspect, we’ve not done the due diligence, but I suspect that there are already companies out there because aspirin has been recognised as… it was probably the first bona fide pharmaceutic actually. Because aspirin has such recognised pharmaceutical credentials there are plenty of companies that have patent protection in this field. So I suspect that our analogue probably does have some patent protection by one of these big pharma companies already.
How would funding work in a preclinical setting?
I suspect it wouldn’t, they wouldn’t fund us to do it. We would have to fund it ourselves probably and that’s what we’ve done thus far. All of our preclinical data has been self-funded through my own research funds actually. But I think there’s potential here, although the chemical structure is not patented the mechanisms of action that we’re defining are probably very novel and therefore have the potential to be patented. So companies moving into this space might effectively be able to create their own patent profile around this type of analogue.
What we’ve also shown, actually, is that you can tweak the chemical structure very subtly and create quite marked changes in the activity of these agents. So it’s highly likely that with a more methodical combinatorial approach to the chemistry we could produce even better analogues that would then potentially be patentable. So this is really a proof of principle approach rather than a sort of drive towards a pharmaceutic.
Until this is produced should someone on FCR be taking aspirin?
All the evidence so far, albeit slightly anecdotally, this is not part of a randomised controlled trial, remember, this was just an observation made with quite a large scale study, actually. Over 300 patients at the MD Anderson in America, they don’t do phase III trials, that’s their modus operandi, they tend to do large scale phase II trials with no comparator arm. But it’s obvious now that we should be doing a randomised controlled trial where we prospectively give patients aspirin up front with their standard of care. Why not? I suspect that unless they’ve got underlying health problems that would preclude them from being involved in a study of aspirin, yes, it would be a great thing to do.
