ASH 2013 - New Orleans, LA, USA

Role of Bcl-2 family in lymphoid malignancies

Prof Andreas Strasser - University of Melbourne, Melbourne, Australia

We work in apoptosis research, research on how cells die normally and how this cell death is relevant to the development of cancer and, of course, how we could activate it to treat cancers. A major interest in the field at the moment is the targeting of the so-called Bcl-2 family of proteins; these are proteins that are essential to keep cells alive, they actually control the cell death versus cell life switch and for two of these proteins, there are five of the pro-survival proteins, for two of them drugs are now in clinical trials. What I talked about today was about another member of this pro-survival family which is called Mcl-1 for which there’s no drug at the moment and our data showed that in certain leukaemias and lymphomas if you target Mcl-1, we use genetic tools to do it, that these lymphomas melt away and that provides indication that drug companies should really try to develop inhibitors of Mcl-1 for cancer therapy.

Are there drugs available either freely or in clinical trials for the treatment of lymphoma?

Targeting of Bcl-2 or targeting of Bcl-2 and Bcl-xL, there are two drugs that are in clinical trials, they’re both in phase II clinical trials at the moment but no, they’re not really available yet.

Do you think these will become available in the future?

Of course, having been involved in this field for a long time I very much hope that they will become available for treatment, that they will be found to be efficacious and safe and that it will benefit many patients’ lives. So, at the moment the trials look good so I’m very hopeful.

Is this only for lymphoma?

Initially it’s for the treatments; they’re being trialled in the treatment of leukamias and lymphomas but ultimately it’s very possible that once they’re approved for the first indications that they will be trialled and tested on totally different types of cancers, non-haematological cancers.

What is the background of the experiments that lead to this discovery?

To study the function of Mcl-1 in lymphomas what we did is we made mice in which we can delete the Mcl-1 gene conditionally with genetic tricks so that’s what we used to prove this discovery that Mcl-1 is critical in the mouse lymphoma settings. For human lymphomas and leukaemias we had to develop a different set of tools and for that what we do is we use so-called inducible expression systems where we generate vectors that allow us to express inhibitors of Mcl-1, highly specific protein inhibitors of Mcl-1, and we found the same in lymphoma cells from humans as we did in the mice which, of course, is very gratifying.

What are the safety concerns with these types of drugs?

Of course the control of cell survival and death is there not only in cancer cells, it’s there in all of our cells in our normal tissues so that’s what we have to look at. It turns out with the two drugs that are in clinical trials so far the safety concerns are not too severe. The drug that targets only Bcl-2 appears to be very well tolerated. The drug that targets Bcl-2 and Bcl-xL, the most obvious concern was a drop in platelets but so far that seems to be manageable in the clinic. The reason for this drop in platelets is actually because Bcl-xL is highly critical for the survival of platelets. So by and large, I believe the concern with all targeting of pro-survival Bcl-2 family members will be where the protein that you target in the normal tissue will be the most important. Of course, if in the normal cells if a cell relies on two different pro-survival proteins to stay alive you might find yourself in a position where if you specifically target only one of them the normal cells will do much better and survive whereas the cancer cell, if it’s dependent on only the one pro-survival protein, then it will have a very good therapeutic index.

Would these drugs be made available to all patients?

Initially certainly in the clinical trials as they’re going on now, they’re reasonably tightly selected patient groups, this is just because of the way the trials are run. So most of the trials at the moment are in chronic lymphocytic leukaemia and the only access to patients that the clinicians have now is patients who have failed prior therapies. But ultimately we hope that it could be going into primary disease presenting patients in this disease and ultimately, as I indicated, I think there might be much wider use of these drugs. The pre-screening that might be helpful is that if you have a drug that selectively targets Bcl-2 then the prime cancers to be treated would be those that have exceedingly or abnormally high levels of Bcl-2, that would be a good indication that they might respond. But, in essence, at the moment you just have to either test the cancer cells’ susceptibility in tissue culture experiments or in animal experiments or in clinical trials in the actual patients. That’s really the only relevant answer at the end.

These are ongoing trials and are still recruiting?

Yes, they’re still recruiting and they’re actually starting new trials now, already starting to expand into other types of cancers but still mostly haematological ones although on the drawing board there are trials in other types of cancers, solid cancers. I know that there will be a breast cancer trial being done with one of the Bcl-2 inhibitors in the near future.