18th Congress of EHA

JAK-STAT pathway in malignant and non-malignant cells in myeloproliferative neoplasms

Dr Ross Levine - Memorial Sloan-Kettering Cancer Center, New York, USA

Dr Levine, thank you for joining us at this meeting of the EHA. I believe you described myeloproliferative neoplasms as clonal chronic leukaemias without curative therapies. Can you say a little bit more about what is obviously a clinical conundrum?

The big issue with these diseases is that patients present with abnormal cells and that although we have treatments which can reduce the problems that these cells cause, ultimately without a bone marrow transplant there is no medication, either chemotherapy or targeted therapy, that can cause remission. So the challenge right now is mostly to mitigate the aspects of disease while we hopefully work towards developing a curative therapy in the longer term.

As I understand it, the data that you presented at this meeting was about how JAK kinase inhibitors can reduce cytokine production with potential benefit for patients. Can you outline this data in more detail for me?

The big thing we wanted to try to do was actually explain in the laboratory something that we see in patients which is that JAK inhibitors, which have already been developed and in one case are approved, have very significant benefits for patients, even though they don’t lead to cure they lead to very significant improvements in spleen size, symptoms, blood counts. The presumption initially when the mutations were discovered in JAK and the targeted therapies against JAK that we were using a medicine that was targeting the mutant leukemic cell. It turns out that both based on clinical observations of these changes in cytokines, and now based on our laboratory work, that the drug is probably targeting both the leukaemia cell and normal cells that are in the mouse or human, if you will, at the same time, suggesting that the drug actually has multiple different targets which is not something that people anticipated but now we’ve provided some mechanistic proof. Clinicians had theorised that this was the case based on what they saw in the clinic but we now give some evidence to support their theories.

So where do you take this research from now on?

There are two fundamental questions: one is to much more precisely understand the mechanisms, to really understand what the drug is doing in different cells, which cells, which cytokines are the most important, to really drill down on the details. But I think the more important question is might similar approaches, targeting not just the leukaemia cell or lymphoma cell or myeloma cell, but targeting those cells and normal cells that are adjacent to that, might that be an approach we can use for other hematologic tumours or other cancers in general? Because this idea that maybe we have drugs that might have multiple targets is one that people have talked about but it would be nice now to probe this more broadly. So we’re hopeful it will be more broadly relevant.

And you’re making progress at your own centre, presumably, as far as this is concerned?

Yes, because of our interest in leukaemias, our predominant approach right now is to look in other leukaemias, acute and chronic. But it’s our hope that some of our work will be taken up by others in other areas and in the longer term, both again in liquid tumours but also in solid tumours as well, which I think is quite interesting and exciting.

Is this research actually being undertaken anywhere else in the world or are you really the centre of all this?

As always there are many groups working on similar areas. I don’t know that anybody is working on exactly this question currently but there are a lot of groups interested in the effects of cytokines on cancer, either from the tumour or from the microenvironment. What I think was different was that we thought studying a drug and its effects on that process would be different whereas a lot of people study the basic process but we were interested in the translational aspects of it, which I think is a little bit different than maybe some of the other people in the field.

So finally, as far as you’re concerned anyway, this is a potentially fruitful area of research?

Yes, we think it’s fruitful in many areas, both in terms of doing a better job of tailoring our therapies for patients with these chronic leukaemias and then obviously extending them to other contexts. So we think it’s just the beginning of a very interesting story.

Dr Levine, thank you very much indeed.

Thank you.