Last month, while talking with Prof. Yayon (one of the world leaders in the research for a treatment for achondroplasia), I asked him about his opinion about the efficacy of BMN-111, and he answered: “Children with achondroplasia have lots of CNP”. Well, … Continue reading →
I contacted Professor Noriyuki Tsumaki, the head researcher for the study of the use of statins in achondroplasia, also mentioned in a post here. I kindly got the following asnwers: “Statins should not be used in children because statins decrease cholesterol, … Continue reading →
The online RE(ACT) Community is organized around four main axis dedicated to research on rare and orphan diseases: Learn, Meet, Share and Support. Learn from the knowledge and experience of other researchers and patients; meet other researchers and facilitate the … Continue reading →
In my last post, about the V International congress around achondroplasia and other skeletal dysplasia, I mentioned the participation of Dr. Elvire Gouze and her lecture. She is responsable for the developement of the soluble FGFR3. Dr. Elvire Gouze was kind to … Continue reading →
A child with achondroplasia has, among other body characteristics, a large and heavy head and disproportional short extremities (arms and legs), increasing the difficulty to control gait. For that, the probability of hitting the head harder while walking, playing or just … Continue reading →
Nature journal published yesterday an article connecting statins to achondroplasia treatment. You can read the abstract of the article “Statin treatment rescues FGFR3 skeletal dysplasia phenotypes“.A. Yamashita et al. Nature,doi:10.1038/nature13775, 2014 Statins or HMG-CoA reductase inhibitors are a class of drugs used … Continue reading →
The last days, I have been doing some research about 3d bioprinting and I´m completely amazed by all that I found. This impressive technic is a huge evolution in medicine and it shows obvious signs that it will, in a … Continue reading →
FGFR3, was many times mentioned here. But probably is an abstract concept to many. I will try to keep it understandable. FGFR3 is the short-term for fibroblast growth factor receptor 3. Is a very studied protein and there is an enormous amount of scientific papers written about it, specially related to cancer, once FGFR3 has intense action in some types of cancer growth.
FGFR3 exists in the wall of the chondrocytes, the cells where lays the genetic mutation for achondroplasia.
Well, imagine the FGFR3 as a wall power plug. Imagine that this wall plug is at the exterior of a garage wall. So, if for example, you need to trim the backyard lawn, you need to connect an electric lawn mower plug to this wall plug. And now, imagine this plug to be one FGF (fibroblast growth factor). And then something happens: an action-reaction. And the mower starts receiving energy and work.
So, FGFR3 will only start its action after some special particles, one FGF, connect with it.
Now, imagine the garage is a chondrocyte, that is the type of cell that exist in the growth plate in the long bones. The garage is surrounded by open space by all sides. In the biologic and microscopic vision, this open space is called extracellular matrix. Even if you observe a live tissue using a microscopic, you will see that each cell seems attached to others. But in a ultramicroscopic vision (a much powerful view), there is a free space between cells, filled with that matrix, and where particles like FGF exist.
FGFR3 exist in the chondrocytes membrane, that is the wall that separates the chondrocyte from the extracellular matrix. When a FGF connects with the FGFR3, it starts a few cascade reactions.
Imagine these cascades as an amount of dominos falling over each other. Imagine the last piece of the domino falling and the result, for instance, is turning off something. So the last piece of FGFR3 cascades (with several factors evolved), end in the DNA of the chondrocyte with the information to the cell stop multiplying and to mature.
Don´t take FGFR3 wrong. It is needed! If not, we would growth too much. It a healthy person, while in a growing age, FGFR3 give signs to reduce growth in a controlled way.
Well, this is like cooking! To much salt and you can´t eat the food. To less, and it won´t taste good.
In achondroplasia, because FGFR3 has a mutation that produces an over expression of it cascades, it acts almost in a continuous way, giving too much signs to the chondrocyte DNA to shut down growth.
The most important FGFR3 cascade for achondroplasia fenotype is one that has a very strange name MAPK (after: Mitogen-activated protein kinase)
So science is in the way to break the FGFR3 effects in achondroplasia by shutting down pieces in the MAPK cascade (also called a pathway).
The particles (correctly they are enzymes) involved in the MAPK cascade are RAS, RAF, MEK1/2 and ERK. Following ERK is the cell nucleus where the DNA is. And the DNA will produce the command given by this cascade: shut down growth.
Imagine them as domino pieces: RAS—>RAF—>MEK1/2—>ERK—>nucleus—>DNA—-> result
For instance, the action of BMN-111 is breaking the MAPK cascade between RAF and MEK. Like if it was a wrecking ball attacking that point. So the MAPK cascade will not reach the nucleus, and the information to stop growing won´t reach the DNA. And the chondrocyte will keep multiplying!
There are several compounds being studied or even in clinical trials for cancer, aiming for the MAPK cascade.
The FGFR3 exists in several types of cells and many types of cancer use the MAPK cascade to grow. And because cancer is such a relevant and frequent disease, the research around cancer pathways is a very studied subject.
There exist some drugs to treat cancer, named anti-RAF and anti-MEK, that will attack that particles of the MAPK cascade. Many are still being studied but others are already used for cancer.
So, the question arise: why aren´t we using those anti-RAF and anti-MEK already available to treat cancer in achondroplasia?
Well, most importantly, those drugs attack all types of cells that carry FGFR3 and that are naturally dividing. So it would be expected more damage that a positive result.
This month, it was published an article about a anti-Mek compound, Selumetinib, that as been tested in some pediatric cancers.
One important observation in this study was that at the growth plate, they observed an increase in the height of the hypertrophic zone relative to the proliferative zone of +78% in PD0325901 treated mice.
If pharmaceuticals start to go forward studying deeper MAPK cascade in pediatric cancer, maybe we can have a shortcut to reach another treatment for achondroplasia besides BMN-111.
To know more, you can read the always updated and easily understandable written blog Tratando acondroplasia, by Prof. Morrys.