Is the inhibition of deregulated FGFRs the next step in treating cancer?

Cancer is a phenomenon that is likely to affect all of us at some point in our lives. In fact, due to the innate inefficiencies in maintaining our genetic code, if someone were to live long enough, it is inevitable that that individual would develop cancer.  It is therefore of crucial importance that new effective treatments against cancer are developed. A recent paper by Chell et al investigates the possible therapy of inhibiting unregulated fibroblast growth factors, a promising development in cancer treatment. 

Fibroblast growth factors (FGFs) function by signalling through tyrosine kinases known as Fibroblast growth factor receptors (FGFRs). FGFRs play an essential role in an organism maintaining its normal cellular behaviour in processes including cell proliferation, cell migration and cell differentiation by producing signals for growth.

In some circumstances FGFRs can become deregulated. Deregulated FGFRs are found in a large number of different types of cancers including breast and gastric cancer. By inappropriately activating FGFRs and the downstream signalling pathways, cell proliferation, survival and invasion are dramatically increased.

Because of this there has recently been a heightened interest in targeting unregulated FGFR signalling in the treatment of cancer by developing FGFR-selective tyrosine kinase inhibitors (TKIs). TKIs are drugs that inhibit the enzymes responsible for initiating the signal transduction cascades that are produced by FGFRs. 

This paper investigates the use of two specific FGFR TKIs (FGFRis). The first being AZD4547, and the second being the molecularly related AZ8010. In this instance these two compounds were compared to an FGFRi that had already been clinically established, PD173074. 

The tumour cells that were very sensitive to the action of FGFRi were found to be addicted to their deregulated FGFR signalling. This makes these tumour cells dependent on that particular pathway for cell proliferation and means that once the pathway that the tumour is addicted to is blocked, it is a struggle for a new alternative pathway to be established. Because of this they become particularly sensitive to FGFRi treatment, making it an appealing therapy in certain susceptible cancers.

If the story were to end here then the treatment of cancer wouldn’t be such a relentless challenge for researchers. However, there has also been evidence which suggests that with this type of treatment there would be a level of acquired resistance brought on by a mutation, making this therapy ineffective.  

To continue their research Chell et al attempted to model this mutation to further understand how resistance is formed. To do this they utilised the fact that the ATP binding pocket in FGFR1, 2 and 3 are highly conserved and used PD17304 in complex with FGFR1 to model the mutation that was causing them such trouble. 

The mutation responsible for resistance was at FGFR^V555M in the ATP-binding site. This point mutation caused valine to be replaced by methionine. This model suggests that the bulkier side chain of Met was restricting access of FGFRis to a cavity adjacent to the adenine ring-binding protein.

In addition to this it was also noted that the equivalent residue of FGFR.Val 561 makes Van der Waals contact with the PD173074. However this isn’t true with the bigger side chain of Met561, a factor in why PD173074 can no longer bind.

This study has given a number of new insights into potential future therapies.

We can see that when FGFRs become deregulated they can act as oncogenic drivers in cancer. More importantly is the fact that some cancers can become addicted to the deregulated FGFRs that promote their high proliferation. This is important in the treatment of cancer as if there is a way of blocking this pathway of proliferation, then no new pathways of proliferation will be sought out by the tumourous cells due to this addiction.

In this particular paper resistance to FGFRis are caused by a gatekeeper mutation called FGFR^V555M. However this isn’t the case in every example of FGFRi resistance, with numerous different mechanisms allowing for resistance to be acquired.

Different FGFRs have been the target of many cancer therapies in the past, and the fact that more inhibitors are becoming available is beneficial, making it even more important that the method of resistance and preventative therapies for that resistance is further investigated. When considering future studies in this field there are a number of things that need to be considered. One of these include attempting to put a timescale on when a gatekeeper mutation is likely to develop in an individual, as well as whether there is a route of therapy where this mutation will not affect the treatment.

However, at this time it may be more important to investigate a second generation of inhibitors. These will become important for when resistance to the first generation forms, making them ineffective. This has already occurred in the case of other FGFR inhibitors that have been developed in the past.

Whilst this could seem like a complicated topic, it is one that must be fully understood to contribute to the advancing field of cancer biology. The inhibition of unregulated FGFRs, whilst not being effective independently could become crucial in the chemical cocktail involved in chemotherapy, which whilst inefficient, is still a lifesaving therapy. 

How do you think this research could be taken further? Could FGFRis be become part of a new treatment used until ineffective until another drug can take its place? Comment below or email newsinscience@gmail.com with your thoughts and opinions. 

Does religion have a place in modern society?

Richard Dawkins is a man who has relentlessly shoved down our throats the idea that religion has no place in the modern world, that it holds us back from our potential, and essentially that anyone who practices it is an idiot.

Once again the well known author and biologist has taken to twitter to tell us that accepting someones religious views is simply preposterous. But is it? Whilst science is giving us more information about the world and universe around us every day, does that mean that every day we lose a piece of our faith in god? For many people the concepts of god and science go hand in hand. Seeing the increasing complexities in our environment leads many people to point to the 'watch maker' idea that something so complex must have had a designer or creator, governing all these various mechanisms.

Others go the other way and think that by explaining the mechanisms that govern biological systems we show them to simply be another step in evolution, and completely detracted from god.

But I think the main point we should be looking at here is, does it matter what someone believes? Aren't we being held back more by those individuals who insist that their view is correct, and everyone else's incorrect? There are people on both sides of the debate, believers and non-believers, who continually attack each other simply because they don't think the same as them. There are valid points on both sides, but neither have produced undeniable proof of either the existence or absence of a god.

Essentially what I'm saying here is, why can't we all just try and get along, let people believe what they want to believe, and keep our opinions to ourselves... especially you Richard. What do you think? Can science and religion coexist? Comment below or email newsinscience@gmail.com with your opinions.

Origin of the word 'sphincter'.

I think it's always fun to learn the origin of a word, so now I'm going to tell you where the hilarious word sphincter comes from. For those of you who don't know, a sphincter is a ring of muscle which expands or contracts depending on its biological need. There are lots of different sphincters in the body but the most commonly associated with is that of the digestive system.

To understand the origin of this word your going to need a bit of a background knowledge on the sphinx, a mythical creature and ruddy great statue in Egypt. The sphinx has the head of a human and body of a lion. Mythology tells us that the sphinx would ask its victims a riddle. If a correct answer was given then the victim would carry on to live another day. However, if the victim answered incorrectly then the sphinx would choke them with their paws until they died. It is this strangling and contracting method which is also seen in the sphincter we associate with our toilet habits, which is how sphinx became sphincter.

Know any other words that have fun origins behind them? Then comment below or email newsinscience@gmail.com to turn it into another blog post.

Did Darwin get too much credit?

Charles Darwin, one of the most instantly recognizable scientific names in the world, is credited with the theory of evolution. A personal hero of mine,  Darwin was initially ridiculed by some, and hated by others for his, at the time, outlandish theory.  However, decades on, the theory of evolution is universally accepted.

A new documentary however has brought the contribution of Darwin into question, and instead puts forward an argument that Darwins friend, Wallace should have received the credit instead.

Presented by comedian Bill Bailey this is one of those rare things, a programme which discusses evolution without simultaneously being mind numbingly dull. A definite must watch for those of you who have ever wondered about our origins. The programme can be found on the link below on BBC iplayer.

http://www.bbc.co.uk/iplayer/episode/p0160p0s/Bill_Baileys_Jungle_Hero_Wallace_in_Borneo/

What are you opinions on this programme? Should Wallace have been given more credit? Comment below or email newsinscience@gmail.com with your questions or opinions.

The Death of Sir Robert Edwards

In terms of darwinian biology, the fitness of an organism is determined by their ability to pass on their genes through the production of offspring. For many reasons however, this is not possible for numerous couples who hope to conceive a child, but who's biology doesn't allow them to do so.

In the beginning of the 20th century if a couple were infertile then they wouldn't have been able to have a child of their own, and that would have been the end of the story. This all changed in 1978 with the birth of Louise Brown, the first child born through a treatment called IVF which produces what is now termed 'test tube babies'.

In the common age, IVF is a common scientific procedure known by the majority of the general public which has resulted in the birth of millions of children. The implications of this have now been overlooked and taken for granted. The fact that children are now born, who would previously have been unable to exist is an astonishing feat in the scientific development of the human race, allowing the previously considered infertile to produce children who share their DNA.

This treatment was developed by a man who millions of people now owe their lives to, Sir Robert Edwards, who died today aged 87. Before his death, Sir Robert was awarded a nobel prize and a knighthood  in recognition of his contribution of potentially the most important practical application of biology within the last 100 years.

Sir Robert once remarked that there was nothing more special than having a child, a belief shared by many whom he helped achieve their life ambition. The field of science and biology has lost a great man today, but his legacy will be carried on in the generations he helped create. 

What are your opinions on this monumental biological development? Comment below or email newsinscience@gmail.com with any questions.