Betablockers repurposed to treat neuroblastoma

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Published: 10 Jul 2014
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Dr Eddy Pasquier - Children's Cancer Institute Australia, Randwick, Australia

Dr Pasquier talks to ecancertv at the Metronomic Chemotherapy Meeting in Milan about drug repurposing with particular reference to the use of betablockers in paediatric neuroblastoma.

I’ve been working on drug repositioning for… originally it was a side project, something that we wanted to test and the result was so good that it has become my main interest. So originally we’ve worked a little bit on breast cancer because the data, epidemiologic data, was pointing towards that direction, that it was something interesting and you always need to get some kind of publication before you can get funding for your project. But the main project was on neuroblastoma, which is a really difficult to treat form of childhood cancer, and we got some very exciting results using beta-blockers in combination with certain types of chemotherapy drugs in neuroblastoma.

You’ve been looking at beta-blockers?

Yes, that’s right, beta-blockers. So they are drugs that are normally used for the treatment of hypertension and they’re quite well known because golfers used to take them in the ‘80s to steady their putt because it makes you very quiet. So there’s some data to show that it was very effective in hemangiomas which are very benign vascular tumours that are very common in infants, one out of three children have that. We usually call them birth marks but they are actual hemangiomas. Usually they regress by themselves but in some cases they don’t. They found that when patients were treated with beta-blockers those vascular tumours were just disappearing, vanishing very quickly. So it has completely changed the field of this type of condition, the way that they’re being treated and, based on this research, Nicolas André and I thought that we should potentially see if there was a role for these beta-blockers in childhood cancer treatment. 

So this is in the early stages?

Yes, exactly. We started this work in about 2010; we have now published our pre-clinical study last year and we‘re hoping to move to a clinical trial fairly soon.

So there’s no evidence in neuroblastoma?

The evidence in patients is very limited because the trial hasn’t started. One of the limitations of this kind of work is because we work on drugs that are off patent it is very difficult to fund this kind of clinical trial because there’s no interest from the pharmaceutical industry to invest in these trials. So the only evidence we have so far is in some instances some neuroblastoma patients, they have a really high level of adrenaline and noradrenaline because of their tumour which is affecting their peripheral nervous system. Because of that sometimes clinicians have used beta-blockers in these patients to control for hypertension during surgery. So from that we know that beta-blockers are safe to be used in neuroblastoma patients. Now what we need to know is if we can translate what we’ve found in the lab in our in vitro and in vivo model into actual patients.

Can you tell us a little about next generation repurposing?

Next generation drug repositioning is some terms that I came up with just two days ago because I was looking for a title for this part of my talk. The ID is… again, drug repositioning is something that a lot of people are interested in because it can cut the cost quite significantly but which drug do you decide to use in the first place? That’s the tricky question. So with the beta-blockers in a way we got lucky, we had a hunch, let’s say, that we thought that maybe it would work and we got lucky, it worked. But how can you go about and really screen for a lot of drugs in an unbiased manner? One way to go about that is to use high throughput technology, high throughput screening technology. So I used now some robotic platforms which can handle liquids and plates and cells and everything at the same time. So in a manner, to give you an idea, the screen that I’ve done where I’ve screened about 3,500 different drugs, this took me about a month to do. If I had to do it manually with an army of PhD students it would probably have taken us five years. So with this technology we can really go much faster and screen a lot of drugs and then make discoveries very quickly and move them rapidly to the clinic because the drugs that I am screening are already approved and we already know their safety profiles, their pharmacokinetics profile. So it makes it much easier to translate into the clinic.

How do you ascertain which genes are being affected by these drugs?

That’s something, it’s a little bit of home cooking, I would say. There are thousands of papers out there describing every single drug that I’m using who over the time have found this particular drug is affecting this gene. There are a few that have a basis that you can use where you can find information for every single of these compounds of all the genes that have ever been described as being affected by this particular drug. Which is what I did and I went through all the compounds that I found that were increasing the efficacy of chemotherapy and found, again in an unbiased way, which are the potential genes that were involved in resistance. Now the work is to try to narrow down to the key genes. Again we can use some robotics and to do some screening of what we call sRNA, which are a small molecule that will knock down the expression of those genes, and to validate those targets. So the idea is you show that a compound is increasing efficacy to chemotherapy, you have a list of potential genes that you think might be playing a role in this new effect and you knock them down one by one and the ones that are actually sensitising the cancer cells to chemotherapy is your new target. So in that way very rapidly you can develop a new treatment with your screening where you have identified your new drugs, and biomarkers to use for patient selection and even potentially for treatment monitoring.

What other drugs are being repurposed?

There are actually a lot of them. It’s sometimes really hard to follow everything that’s happening. One of the big things at the moment, and some people talked about that during the conference, is the statins which are also very interesting. Funnily enough there’s now new data showing that statins together with beta-blockers might be interesting. We get to the point that there may be even ways to do some maintenance therapy without any chemo drugs at all and just using some repositioned drugs. Hopefully the screens that I’m going to do are going to come up with even new drugs that we had no idea had an effect in cancer patients. But so far, between aspirin and the COX inhibitors and the statins and all of these compounds, the list goes on and on of compounds that we had no idea could be effective in cancer patients.

What about beta-blockers as prevention?

I think it’s a very interesting area to work on. So one thing that I’m quite fascinated about is if you look back into some clinical trials, the studies that they’ve done about breast cancer screening. In most countries it’s advised for women to get screened from the age of 50 or 55 years old. At some point they wanted to decrease that age of screening and in the UK they went all the way to 35 years of age. When they did that they realised that the impact of the screening was actually negative because what happens is that when you do this kind of systematic screening you’re going to identify some very small tumours that would maybe have remained dormant or would have been controlled by the immune system. But the patient gets diagnosed with a small breast cancer, starts stressing a lot, which is normal because it has a massive impact on their life, and that stress can actually drive and promote the tumour growth. That’s where the beta-blockers have a role because they block this effect of stress on tumour growth. In that sense, in terms of breast cancer and even prostate cancer, that could be very interesting in terms of preventing the development of cancer. That’s something that I’m not personally working on because I don’t work in this area but I believe there will be very soon, and probably people are already working on this, because all the data points in that direction. People who are treated for hypertension with beta-blockers, when they do eventually develop a breast cancer, they do much better than the others. So clearly there is some preventive effect of the beta-blockers beyond what we’ve demonstrated which is when you combine them on purpose together with chemotherapy you also get some benefit.