There are several news reports out today about a new way of turning off cancer causing proteins. These reports are based on a study in the journal Nature called “Direct Inhibition of the NOTCH transcription factor complex“, you will need to pay to read the article in it’s full technical detail, but there are several good summaries on BBC News (”Cancer protein can be disarmed“) and NHS Choices (”Experimental protein for leukaemia“). There is also a good write up in Science News Daily “Researchers “notch” a victory towards a new kind of cancer drug“.
First things first what does the title mean? Direct inhibition means turning something off. The “something” in this case is NOTCH. Notch is just a name of one of the thousands of proteins that are in your body. You have lots of different proteins in your body, they all have different names, ones you may have heard of include insulin or collagen. Transcription factors are a name for a large group of proteins that bind DNA, you have about 2,600 transcription factors in your body (you can read all about them on Wikipedia). You need them to live, in fact, you need them at the very earliest stages of development in order to make a embryo. As the title suggests, these transcription factors don’t work alone, they usually bind a whole host of other proteins and when you get lots of these proteins all stuck together it’s called a “complex”. Basically, because it’s complicated. Complexes can change over time, that means they can contain different transcription factors and do different things.
So what is transcription? Transcription is something your cells do every day, it means taking the information in genes (DNA) and using it to create RNA. Your body then uses this RNA to make proteins. The actual act of transcription means taking information in one form and converting it to another e.g. taking a dictaphone message and typing it up into a letter or taking DNA and converting it to RNA.
So how do you convert DNA to RNA? Well first you need to turn your gene on, this is where your transcription factors come in, transcription factors turn genes on (and off). They do this by binding to DNA and changing it’s shape. Normally this works fine, but occasionally one of these transcription factors can become damaged and you can develop cancer. If your Notch transcription factor is damaged you can develop a very specific type of leukemia called T-cell acute lymphoblastic leukaemia.
Many scientists are trying to find ways to “disarm” or “neutralise” damaged transcription factors, not just Notch, but it has proved incredibly difficult to do. That’s why this new research paper is exciting, they describe a new way of disarming transcription factors that should work on a whole range of transcription factors (not just Notch and T-Cell ALL)
So what did they do? The scientists made tiny, short, protein “staples”, these staples are small enough to get inside cells and in the same way as a key is specific for a lock, these “staples” only bind to the Notch transcription factor. When these staples bind to Notch they stop the “complex” and this stops the leukaemia cells growing, in a laboratory dish and in mice. These experiments have NOT been tried in humans.
What does this mean if you are currently having treatment for ALL? This research doesn’t alter any of the current chemotherapy treatments for ALL. None of these experiments have been carried out in people, and as it is a very new way of targeting proteins it will probably be several years before the scientists are able to try this experiment in humans. It does however give us hope that in the next 10-20 years new drugs will be available to treat some specific types of cancer, like ALL. As these are very targeted and specific therapies (i.e. I would expect these staples to work on Notch, but not other transcription factors) they should have a lot less side effects than conventional treatments like chemotherapy.
Why was I interested in this paper? I spent several years working on different transcription factors and I know this sort of work is difficult, I hadn’t heard of the technique of using hydrocarbon staples to stabilise peptides (short bits of proteins) before. In theory using short peptides is a good idea as it means you can devise very specific treatments but in practice short peptides wriggle around too much and get broken up to easily to be useful as a drug inside a cell. I also know that transcription factors are important in many (if not all) cancers, for example p53, which is why any new technique that means we can develop drugs aimed at transcription factors is a good thing.
Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, & Bradner JE (2009). Direct inhibition of the NOTCH transcription factor complex. Nature, 462 (7270), 182-8 PMID: 19907488