ASH 2013 - New Orleans, LA, US
Targeting tyrosine kinase receptors to tackle CML
Prof Michael Deininger - University of Utah, Salt Lake City, USA
I spoke about targeting tyrosine kinase receptors in myeloid malignancies, so that was basically an overview over currently available drugs to treat chronic myeloid leukaemia, the limitations of these drugs, the successes that we have seen, the challenges that we still have to overcome. And then I tried to take the theme to other myeloid malignancies such as myelofibrosis, acute myeloid leukaemia, really trying to see where this field is going.
Tyrosine kinases, there are many, many… there are about 94 or 95; about 60 of those, 60-70, have been somehow implicated in cancer, many also in hematologic malignancies. There are several tyrosine kinases but really not just these that are currently explored as therapeutic targets. The most well-established one is BCR-ABL 1 in chronic myeloid leukaemia. There’s another one called JAK2 which is frequently mutated in myeloid proliferative disorders such as myelofibrosis. Then we have a number of other kinases that have also been implicated and where inhibitors are currently in development.
What are the inhibitor agents that are available at the moment?
For CML you may have heard about a drug called Gleevac that’s been around for a long time now. There are second generation inhibitors that are built on the success of Gleevac available now, even third generation inhibitors. So these drugs have various spectra of indications. So imatinib, the oldest one, Gleevac, is very effective but there are somewhat better drugs now available to improve on responses. The interesting idea now is to see whether these improved responses will eventually translate into the ability to discontinue treatment altogether but that’s still a little early to make a call on.
What is the problem with existing drugs? Resistance?
Some patients will develop resistance but it’s really a minority in chronic myeloid leukaemia. Some patients will achieve a response but not quite as profound as we’d like there to be, so not profound enough to be able to discontinue treatment or even to consider that. But one has to say that all in all chronic myeloid leukaemia is a big success story so all the available drugs are very potent and there’s only a minority of patients who will eventually fail. The situation is very different in diseases like acute myeloid leukaemia where the survival rates, if you look really globally, are much lower than in CML, maybe only in the range of 20-30% long term survival. These diseases also have activated tyrosine kinases but currently available drugs are not as effective as imatinib in CML, for example. So the question is why is that – does it have to do with the disease? Is it just differently structured? We believe so, that that’s the case, but there may also be a contribution from the inhibitor design such as they may not be optimal, they may not be potent enough, they may not be selective enough or maybe they are over-selective. So both of these areas are subject to intense research. They’re not even approved for AML, they’re not used in first line. The only myeloid disease… not the only one but one other major myeloid disease where TKIs, tyrosine kinase inhibitors, are being utilised is myelofibrosis. In myelofibrosis it’s a slightly different situation because these drugs are very effective in improving symptoms but they are certainly not curative, they may prolong survival a little bit but it’s nowhere near to the CML situation. Again this has surely to do with different disease biology. In other words, the whole field is diversifying and we are identifying more and more the specific molecules that are suitable for a specific patient population.
Will you select which patient population will receive a specific type of tyrosine kinase inhibitor?
In CML it’s easy because there is only one molecular lesion that we know about that is really required to produce the disease, it’s called BCR-ABL. So if you make the diagnosis of CML you have basically most of the knowledge you need to pick one of the drugs. I think there’s more granularity to that, so certain mutations may arise that may drive the selection of certain second or third generation inhibitors. In other diseases the disease entities are much smaller. So, for example, there are diseases with rearrangements of a tyrosine kinase called PDGF, platelet-derived growth factor receptor. So unless you know that somebody has a mutation of this particular kinase, it’s not really advisable to just try one of these drugs. However, if you do know about it then you can pick an inhibitor that’s going to work for this particular individual. So it’s a work in progress, we’re not quite there yet but what we see is there’s tremendous molecular diversification and superimposed on that is an increasingly broader spectrum of available inhibitors. So if you can match up the two very well then I think we’ll really be able to move towards personalised therapy in cancer.
