Targeting the NEDD8-activating enzyme to induce apoptosis in CLL cells
Dr Alexey Danilov - Oregon Health and Science University, Portland, USA
Could you please tell me a bit about your research that you’ve been presenting at the conference?
My group has been developing approaches to target the microenvironment in Chronic Lymphocytic Leukaemia. There have been a lot of advances in therapy of CLL in the past few years with novel targeted agents, including ibrutinib and idelalisib which have been both approved for this disease. So those agents target the B-cell receptor signalling pathway which is induced by the microenvironment in CLL, including nurse-like cells, T-cells, dendritic cells etc. in the lymph node. However, there are a variety of other signals which BCR inhibitors do not target, again presented by those same cells. Many of them go through the tumour necrosis factor related proteins such as BAFF, APRIL, CD40 ligand. Those are the pathways which we are trying to target. So, importantly, many of the signals converge on the so-called NF-kappa B pathways and many oncologists would know what that is. This pathway is highly activated in the sanctuary, in the lymph node. BCR contributes to its activation, however, those other molecules and secreted molecules also would. As we are heading into the era where targeted therapies with BCR targeting agents are becoming standard of care, I think it’s really time to think how we can cure the disease, how we can eliminate many of the signals. I think one of the approaches to do that is to target NF-kappa B activity.
We have used several approaches and the approach which we presented here is using a neddylation inhibitor called MLN4924 or Pevonedistat which is from Millennium and now Takeda. We have quite successfully abrogated the stromal microenvironment which we first modelled in a petri dish and then abrogated that using this drug. We abrogated the NF-kappa B activation induced by this synthetic microenvironment. So in this setting CLL cells are sensitised to the novel BCR targeting agents as well as Venetoclax, a BH3 mimetic which targets BCL-2. So while this is all preclinical data I think overall this is a very promising approach which has its future.
And what are the next steps in your research?
There are several next steps. Certainly there are a lot of questions which need to be answered: how does targeting neddylation affect the immune cells in CLL, how does it affect normal immune cells? What are the other mechanisms in terms of how a cell interaction, CLL cell interaction, with the microenvironment support cells is affected? Finally, what would be the effect in vivo? What we certainly would like to do is conduct clinical testing of this drug in CLL. There have been reports of clinical trials with MLN4924 in acute leukaemia so this wouldn’t be a first in human study and we would certainly like to do this analysis.
And do you have a take home message?
I think the take home message is, from what we see now in in vitro studies, is that the future of CLL therapy is in combinations. As this is the kind of disease which is not characterised by a single driver mutation, for example, contrary to chronic myelogenous leukaemia where Bcr-Abl is extremely important, it’s a case of oncogene addiction which is targeted by Gleevac and other drugs which inhibit the Bcr-Abl function. So in CLL there is no such driver mutation and there is a substantial clone heterogeneity. So targeting multiple components of the support system in the microenvironment is the way of the future where we could potentially cure this disease.
