Basically two different types of cell death, ways that cells die, and this can be relevant to chemotherapy, radiation therapy or really any way that a cell can die. There are fundamentally two different pathways of cell death: cells can die by apoptosis or cells can die by necrosis. In one form of necrosis which has been nicknamed necroptosis, because pretty much we have to rename things or else people know what we’re talking about, the process of apoptosis which involves caspase proteases actually antagonises the process of necroptosis. The outcome of that process is that if we remove this particular apoptotic process, this particular caspase, mice don’t develop. You don’t get a mouse if you remove, in fact, any part of that complex of proteins. If you remove the necroptosis mice develop but there’s no particular change in the development of the animals. If you put both of those together whereas you would have had a dead mouse now you actually have a perfectly normal development. What this is telling us is that these are very fundamental processes to development and, now we know, also in the adult in homeostasis. So now the issue becomes how does this necroptotic cell death occur and what real functions does it have and that’s really where I’ll go into the depth in my talk.
At what stage is the research?
There are no clinical trials at this point. We’re really at the earliest stages; not only our lab but several labs are developing drugs that either block this process or engage this process of necroptosis. That will give us the opportunities now to really explore to what extent can this form of cell death be exploited or prevented in pathological situations.
How does this affect the other type of cell death?
Basically it’s that intense interface between apoptosis and necroptosis that allows us to switch back and forth between the two modes of cell death in some settings. But it’s interesting that there are also mechanisms that can only engage part of the apoptotic process without killing the cell and actually block the necroptotic process and so you get cell survival. This gives us clues to the way we can disrupt just parts of the system to switch a cell into a particular mode of cell death.
Is there any danger in harming non-tumour cells?
There’s always that danger and at this point we’re not really sure that this is a therapeutic window. To give an example of the sort of excitement that’s going around this, many, many years ago, probably more than twenty years ago, there was a notion that we might be able to engage one particular pathway of apoptosis, the so-called death receptor pathway, in treatment for cancer. This is actually still going on for some of the death receptors but others have been excluded quite a long time ago. One of the things we knew was that if we blocked the caspases that were engaged by the death receptors then the apoptosis wouldn’t occur. We know in mice and now actually in people that these caspase inhibitors used at relatively intermediate doses or even high doses will block the apoptotic process engaged by death receptors. Well now we know that it can also open or engage this necroptotic (I hate the word, but that’s how we are) the necrotic process through this other pathway. That creates a really unusual opportunity because nobody would have dreamed even five years ago of trying to induce cell death by blocking caspases rather than engaging them. So we’re at very early days to try to understand that and try to exploit that in these sorts of applications.
How does this tie in with the theme of personalised medicine?
Two things; so how do I feel about personalised medicine? I think it’s inevitable and it’s actually a great step forward that in time we will personalise every patient, as I think happened a century ago, we’ll come back where every patients is treated as an individual and that the specific disease is now defined in molecular terms. That now opens the opportunities for pharmacological intervention. We’ll stop defining cancers based on the histology of the cancer or nomenclature of histology and move towards a molecular definition of cancer and thereby hopefully the dream is, of course, a pharmacologic definition of cancer. That said, I don’t know that that’s the only way that we can move forward. I still believe that the possibility exists that, at least for broad types of cancer, there may be broad therapies that we still haven’t explored. Remember it’s only a few years ago that we drugged for the first time a protein-protein interaction - the inhibition of the BCL2 family which still has enormous application potential and potential application. We’re learning how to drug protein-protein interactions and when we get to that point that those can be done I do think it opens up great opportunities. We’ve heard about some of them here which would be more general treatments rather than personalised.
With respect to what we’re working on, we’re really at such an early stage and at such a fundamental level I don’t know when or where we’ll begin to personalise this. We don’t really understand how this form of cell death occurs. We do know that some cancer cells can engage it and some can’t; some aspects of the pathway are actually disrupted in some cancers and that makes sense, that you avoid dying if you’re a cancer cell. But, again, that would be a form of personalisation - if the cancer can have necroptosis engaged it may present opportunities for us to then engage that pathway and kill the cell. It has another feature as well, which my colleague Guido Kroemer will talk about, that this form of cell death also has the potential to be more immunogenic, to engage the immune response to a greater extent than apoptotic cell death might. Again, I think that presents certain opportunities for therapy.
