Dual mTOR inhibition effective in reducing tumour load in CLL

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Published: 30 Apr 2015
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Dr Emilio Cosimo - University of Glasgow, Glasgow, UK

Dr Emilio Cosimo speaks to ecancertv at BSH 2015 in Edinburgh.

Dr Cosimo discusses the use of dual mTOR inhibition as an effective therapeutic approach for reducing tumour load in chronic lymphocytic leukaemia (CLL). He also speaks about the data showing inhibition in phosphoinositide 3-kinase (PIK3) and bruton's tyrosine kinase (BTK) through drugs such as idelalisib and ibrutinib. He warns of the evidence showing increased resistance to these drugs, concluding that the dual mTOR inhibition is a good alternative treatment singularly or in combination.

Today I presented some in vitro/in vivo data which we developed in the lab about a novel therapeutic drug, which is called AZD8055, to inhibit the mTOR, the kinase catalytic domain and therefore inhibiting both complexes of mTOR, mTOR1 and mTOR2. We think that’s superior to the previous inhibitors such as rapamycin or the analogues of rapamycin called rapalogues which inhibit only the mTOR1 complex, then leaving the mTOR2 free and released from the negative feedback loop of mTOR1, therefore then signalling and pushing the cells into cell proliferation and survival.

What were your findings?

First of all in the poor prognostic patients, 17p deleted and 11q deleted patients, cells from the peripheral blood some of the targets of mTOR1, such as phosphatase 6, they were lower and also phospho-Rictor which is also a target of mTOR1 was lower. That was a nice reflection of both proteins. But crucially the phospho-AKT which we think is a crucial factor for survival in CLL cells was sustained in 17p and 11q. When we treated the cells in vitro there was a significant reduction in cell viability with this drug but this additional viability was lost when we used models to mimic the microenvironment in the lymphoid organs, which we call the CD40 ligand 4 or BCR, we lose the cell viability effect, reduction effect, of the drug.

So we also looked at signalling pathways through western blot analysis, so looking at protein levels, and we saw the drug hit the targets, all the mTOR1 and mTOR2 targets as it should. So it’s working fine from that point of view. But we had a look at the key factor, survival factor for CLL, it’s called Mcl-1 which is a member of the BCL2 family and is a pro-survival factor. It has been associated with CLL resistance, drug resistance, in clinical trials. We saw that this drug doesn’t particularly target very well in this CD40 microenvironment, it doesn’t target Mcl-1 at all. But, on the other hand, when we stimulate the cells with a different microenvironmental signal which is called BCR engagement through IGM stimulation, we saw there was a cell viability reduction with the drug and when we looked at the western blot and saw the cell signalling we saw the targets were still hit as they should. More importantly, Mcl-1 was inhibited so there were much lower levels of Mcl-1 in the treated cohort than in the untreated cells. So we have this type of indirect evidence showing that we think that Mcl-1 inhibition is crucial when we look at microenvironmental interactions for the cells to respond to this drug.

Do you think that this might lead to the development of novel therapies?

Yes. In fact, this particular drug, AZD8055, is not going to make it to clinical investigation because it has been refined, as a molecule, by AstraZeneca through a different second generation which is called AZD2014 which is currently used in phase I in solid tumours. We suspect it will be just a matter of time that it will be tried in leukaemias and CLL particularly, which is a good candidate because we saw, and I showed in the talk as well, by our data that mTOR signalling is disregulated in CLL compared to normal cells.

What would you like doctors to take away from this?

The message would be that although we heard a lot of discussion in this meeting about PI3 kinase inhibition and BTK inhibition through drugs such as idelalisib and ibrutinib, which has been very successful, but we are already seeing reports showing early drug resistant developments from a few patients, but still they’re already developing resistance after two to three year follow-ups. We think it’s just a matter of time, these patients might develop resistance and there will be more patients develop resistance to this novel drug. So we believe that the dual inhibition mTOR is a good alternative as a single agent, perhaps, but more importantly in combination to give an extra option for these unfavourable prognostic patients.

Anything else you would like to add?

We don’t have only an in vitro study about this type of drugs, we also have tested the efficacy of this drug in an in vivo environment in actually a CLL-like mouse model which replicates the poor prognostic subset which we’re talking about, about 11q and 17p deleted patients. In this mouse model we have a dramatic decrease of tumour burden in the lymphoid organs – bone marrow, spleen, lymph nodes and blood – compared to untreated. So we think that we don’t have just the proof of in vitro but also from the in vivo studies which are more close, if you wish, to the human body, although it’s still a newer model but it’s a much closer step to a clinical stage for this drug.