Science Interviews


Sat, 8th Nov 2014

Bill Sellers - Targeting cancer

Bill Sellers, Novartis

Listen Now    Download as mp3 from the show Targeting cancer genes

Kat - As we just heard from Elaine, DNA sequencing technology is enabling us to uncover the genetic faults driving an individual person's cancer, and target them with specific drugs. Many of these drugs are showing impressive effects in clinical trials, and some have been licensed for use for patients on a wider scale. But all too often - after months or even years - the cancer comes back, because the cancer cells have evolved resistance to the therapy.

Bill Sellers, lead for oncology drug discovery at the company Novartis believes - like many in the field of cancer research - that the way to overcome this resistance is to use combinations of drugs. I spoke to him after his lecture at the NCRI Cancer Conference, to discover more about these targeted therapies, and the best way to mix and match them to bring forward meaningful cures.

Bill -   The paradigm that began with Gleevec, which is a drug that treats a disease known as chronic myelogenous leukaemia or CML.  The discovery there of a chromosomal abnormality or genetic alteration that activated a gene in that disease happened several decades ago and that eventually led to the discovery of a drug that could turn off that gene.  That gene is called Abl, the genetic alteration turns Abl on, you get cancer.  The drug turns it off.  You give that drug to people, the cancer goes into remission and people have really been now sort of experiencing normal life expectancies on Gleevec.

Kat -   That sounds fantastic that from treating this disease, we have a drug that has really saved many thousands of people’s lives around the world.  Why can't we do this for all other cancers?

Bill -   Yes, that’s a great question.  This disease I described – CML – turns out to be less complicated than your more common tumours like lung cancer or breast cancer or colon cancer.  In those instances, the genes in those cancers are more disregulated or more mutant than in the first disease, chronic myelogenous leukaemia.  So, resistance to the drugs can happen much, much faster.  So, that’s one of the big problems.  And then the second is, we still don’t know all the genes we need to turn on or off in these other cancer types.

Kat -   So, we’ve seen in recent years a new breed of targeted therapy starting to come into the clinic.  We may refer to them as smart drugs or drugs that are designed, like Gleevec, to target a specific genetic or molecular fault in a tumour.  Where are we with these drugs and what are the problems with some of them?

Bill -   So for example in lung cancer, there's a drug that treats a gene known as the EGFR gene or EGFR mutation.  There's another couple of drugs that treat a form of lung cancer that has a gene called ALK.  In each case, those drugs work, but they only work for a limited period of time and then patients relapse.  And patients relapse because they develop new mutations that create resistance to the first drug.

Kat -   This is the idea of cancers almost evolving to get away from the therapy.

Bill -   Yeah, it clearly evolves and we see that evolution in real time.  So, the key there now is to try to find second or third drugs that also pin the cancer down to a point where they can't escape through a simple evolutionary path, and make the evolution to a resistant state basically impossible for the cancer.

Kat -   So, tell me a little bit about what you're trying to do in tackling resistance to this drug, Gleevec, or drugs that work in a similar way to it?

Bill -   The first is that, we believe we now have better and better tools to study resistance in the laboratory and really predict resistance mechanisms that will be seen in humans.  In the past, with chemotherapy, attempts to study chemotherapy resistance in the lab really never yielded anything that was of much benefit in humans.  But now, especially in the case of Gleevec, we’ve seen we can really model experimentally the resistance in the lab and it will replicate in the human.  So, that gives us the ability now to say, “Well, how can we, in the lab prevent that from happening?”  So, we’re using various large scale genomic methods to tackle that problem in the lab and then study patient samples to see if those mechanisms are taking place in the patients.

Kat -   One of the ways I like to think about almost is, it’s like a river and you dam it in one place with a treatment and it finds a way to get around.  But if we can work out how to dam the path that it would take, is that the kind of approach you're talking about, finding two, maybe even three drugs that will just stop it in its tracks?

Bill -   Yeah, that’s exactly the idea.  Some people have drawn an analogy to the treatment of AIDS where the virus was evolving, and it wasn’t until they had three drug regimens that they had a regimen that stopped the viral evolution.  Now, AIDS patients are very well treated with the combination approach.  So, we also know in tumours that we have been successfully treating diseases like lymphoma, usually, you need more than one drug, often, two or three drug regimens are required.  So, we think in these cases that we were talking about earlier, EGFR in lung cancer, we need to go beyond the single drug treatments and find the two or three that are going to – as you said, completely block the river.

Kat -   We know that the drugs we have, have extended life as you say and that the idea of the ‘magic bullet’ cure for cancer is probably fictional.  But do you hope maybe even in your lifetime that there’ll be some cancers that with the right combination of drugs, we can cure?

Bill -   I'm sure of that.  I don’t have any doubt about that.  First, because of the sort of things I've been talking about.  But if you look over the last year, there's been progress on more than one front against cancer.  So, there's the part I talked about which was drug discovery against the genetics of cancer.  But then there's immunotherapy, which really has been validated over the last year or so as having a significant therapeutic benefit.  And then there's things like antibody drug conjugates and just biologics in general.  All of these now are validated ways of having significant therapeutic effect.  Yet, none of those have begun to be really put in combination yet.  So, I think with that kind of sort of weaponry based against cancer, I think – I have a lot of hope that we’re going to make huge progress over the next 5 or so years.

Kat - That was Bill Sellers from the company Novartis.

Kat - That was Bill Sellers from the company Novartis.


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Here's a controversial response.

Cancer research is very interesting as it takes us into the fundamental mechanisms of living cells and demands a whole lot of fascinating stereochemistry, but is it all useful?

Having eliminated most infectious diseases, and having the capability to eliminate hunger, we are living in an unsustainable world where our survival depends on burning fossil fuels to supply the fertilisers and power the sewage plants we need to maintain an increasingly elderly and unproductive population. A small change in the world's climate, which is inevitable, will cause untold hardship to millions of our descendants.

So what, overall, are we trying to achieve? By avoiding one cause of death we increase the probability of another, and add to the potential burden of incompetent, incontinent old people on every aspect of our finite resources. At what point should we say "no more" and allow ourselves and our fellow citizens to die a dignified death  instead of spending months or years drugged to the eyeballs and shuttling between hospitals until someone decides to dehydrate us?

I'd like an answer, because as my 70th birthday approaches, I need to plan my exit strategy and explain it to those with a legitimate interest. alancalverd, Fri, 14th Nov 2014

"Advance directive" ? ...

or get a tattoo  ...

IMO people in the UK should be more concerned about being denied treatment by the NHS, (whose function is to minimize the cost of illness to the state) , rather than worry about the possibility of having treatment administered against their wishes ,  as the former is the more likely scenario ...

Re : RD, Fri, 14th Nov 2014

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