Metabolic vulnerability in NOTCH-driven T cell acute lymphoblastic leukaemia

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Published: 24 May 2019
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Dr Etienne De Braekeleer - Wellcome Sanger Institute, Cambridge, UK

Dr Etienne De Braekeleer talks to ecancer at the European School of Haematology (ESH) meeting: International Conference on Acute Lymphoblastic Leukaemia about metabolic vulnerabilities that exist within NOTCH-driven T cell acute lymphoblastic leukaemia (ALL).

He explains the importance of using genome-wide CRISPR screens to identify new targets for relapsed and refractory ALL and more specifically, NOTCH-driven T-cell ALL.

Dr De Braekeleer discusses the role of NADK in this pathway and future efforts should be focused on elucidating the relationship between NOTCH and reduced ROS levels in ALL.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

My presentation was talking about the fact that nowadays the current treatments haven’t really evolved since the last three decades, causing the problem that a lot of patients that are either refractory to the treatment or are relapsing have absolutely no solutions. So my goal was to find new therapeutic targets and the best way to find new therapeutic targets is to interrogate the genome by performing genome wide CRISPR screens. With this technique you can actually interrogate the genome and turn off one by one the different genes of the cancer cells. You, in the end, find out which genes are essential for the cancer cell to continue to live or to proliferate.

From there I found different types of genes, tried to find genes that would be very targeted for a specific type of leukaemia, so in this case T-ALLs that are driven by NOTCH. From there I tried to compare to other types of leukaemias and also normal cells to see if by turning off these specific genes I was only harming the NOTCH driven cell lines or NOTCH driven cells compared to normal cells. You then limit the number of genes. From there the interesting bit is not to satisfy yourself by only showing this data, you try to explain why this cancer cell needs this specific gene or this specific pathway to be able to continue to progress.

So that’s how I found NADK and, in fact, a lot of different genes that are implicated in the mitochondrial mechanism/metabolism. I used a drug that was commercially available and starting to show that it has a very specific role in the ability of NOTCH driven cells to be relying on these genes or on these pathways to be able to proliferate.
What was the drug that was used?

The drug that I used was thionicotinamide. Unfortunately, the potency of that drug is not that great but it does show a mild effect. So there’s always a possibility to try to improve this initial molecule to make it more efficient or use it with other known therapies that would be making the treatment more efficient.

What is the activity of NADK and NOTCH signalling?

This hasn’t really been shown yet. What has already been shown and what I proved also in my talk is that when you initiate the response by NOTCH, if NOTCH is over-expressed or activated or reactivated, you have a reduction of the ROS levels in the cells. If you block NOTCH you then have an increase of ROS levels into the cell. The role of NADK is to produce the metabolites that will be used to detoxify ROS. So it seems there is, in a way, a connection, a correlation, between the activation of NOTCH, NADK and the reduction of ROS levels in the cells.

Is the role of NOTCH specific to T-cell ALL?

For the moment I only observed in T-ALLs but it’s true that NOTCH has a role in breast cancer and other types of cancers. The problem with NOTCH is that it has a kind of ambivalent role so in certain cancers the over-expression of NOTCH is beneficial for the cancer cells and in other cancers the repression of the receptor NOTCH is going to be beneficial for the cancer cells. So, for example, in oesophageal cancer the repression of NOTCH is actually what drives the oesophageal cancer to progress.

What are the next steps?

The next step is try to understand why NOTCH is so dependent on having ROS levels so low. Is it because they are using a specific pathway that produces more ROS than other cell lines or other types of cancers? And try to see how it fits all in the metabolism and what has already been shown. So Adolfo Ferrando showed that the glutamine pathway is very important for NOTCH driven cell lines; it has also been showed that the heat shock proteins are also important for NOTCH driven cell lines. So try to see how what I found is able to fit between these two stories.