EHA 2015

Recurrent mTORC1-activating RRagC mutations in follicular lymphoma

Dr Jessica Okosun - Barts Cancer Institute, London, UK

Please can you tell us about your abstract and presentation on follicular lymphoma?

Follicular lymphoma is the commonest indolent non-Hodgkin’s lymphoma and it’s a germinal centre B-cell lymphoma. Having said that, a lot of the patients that we treat, we treat them with combination chemo-immunotherapy but patients relapse multiple times. We’ve not had any good therapies that have emerged since rituximab. So what we did in this study was to examine patients by sequencing them to see if we can unravel new biological targets. Overall what we found was there is a specific gene called RRagC which is present in about 20%, up to 20%, of patients with follicular lymphoma which is very exciting because this is a potentially new biological target that we can direct therapy towards.

Have new sequencing techniques helped you uncover more targets?

Nowadays we’ve improved the technology quite a great deal, we now use next generation sequencing technology. This really allows us to look at the tumour in greater detail. So what we do is we used something called exome sequencing which allows us to look at the majority of the coding components of a patient’s tumour and this allowed us to identify this particular gene called RRagC that was mutated in this proportion of patients. So it’s quite an exciting time because this technology is really improving our understanding of the genetic landscape of the disease.

Is looking at RRagC mutations in this setting novel?

So what we found, much to our surprise actually, so we screened just a cohort of five patients and in these five patients four out of the five had mutations in RRagC and this gene has never previously been described or attributed to any particular cancer type. What was quite interesting was we looked at other lymphoma subtypes and this was very rare or absent in the majority of them. So it seems very unique for follicular lymphoma for reasons we still do not know why.

How does this relate to mTORC?

In the last few years we’re beginning to get a better understanding of the mTOR pathway. So we know the mTOR pathway is important for tumour growth and tumour survival. But this pathway depends on quite a lot of factors and particularly things like nutrients like amino acid. So the RRagC component really fits in to the amino acid arm of the mTOR pathway. Now, in normal cells what RRagC does is it binds to a partner called RRagB or A and what it does is it allows the mTOR pathway to first of all sense that there’s enough amino acid in the cell and turn on the pathway. So, in other words, if you are a cell that doesn’t have enough amino acid you shouldn’t really be turning on the pathway because you are nutrient deprived. But what we found in follicular lymphoma is that the mutations in some way bypass the need for amino acids so you can essentially continuously turn on the pathway, the mTOR pathway, without having amino acids present, suggesting that the mutations were activating.

Can you tie this together and tell me about the clinical implications?

What’s exciting, I guess, about this data is that in follicular lymphoma, for example, we have not really developed any new targeted therapies. The fact that the mutations are what we call clonally represented, so they’re in the majority of the tumour, it’s present in a lot of the disease events and the fact that they’re activating the gain-of-function mutations, there are obviously a number of mTOR inhibitors already out there and we can begin to see now if these RRagC mutations can act as potential biomarkers for which patients might be sensitive to mTOR inhibitors. So I think it’s quite exciting data because it means that we might be able to stratify our patients better with the use of this potential biomarker.

Is this the future of therapy for follicular lymphoma?

I think it will be for certainly a proportion of the patients, because of course not all the patients have the RRagC mutations. But I think that we hope that that will be the case.