What does cancer have with achondroplasia (ACH)?
Cancer has multiple faces and new medicines to fight this challenging disease (or diseases) are being designed now to block the mechanisms by how cancer cells are able to stay alive, to multiply and to spread throughout the body (metastasize). It is not surprising to learn that the mechanisms used by cancer cells to do so are the same of the normal cells, although in a disproportionate intensity.
For instance, cancer cells take advantage of the functional properties of the cell receptor enzymes such as the fibroblast growth factor receptor 3 (FGFR3). As you may remember, in ACH, the excessive activity of FGFR3 reduces the pace of chondrocyte proliferation (multiplication) and differentiation or hypertrophy (maturation), which in turn leads to bone growth arrest. In some types of cancer, such as multiple myeloma and bladder cancer, the activation of FGFR3 leads to exactly the opposite effect: sick cells multiply freely and the cancer grows non-stop.
Knowing that enzymes like FGFR3 are used by cancer make them natural targets for new therapies. In this way, ACH has been benefiting a lot from cancer research.
We will be looking at cell reactions here and the text may be not like a chocolate cake recipe, so we will walk step-by-step and I will try to illustrate as much as possible to make it easier for the reader.
We have already learned that we can block FGFR3 outside the cell with antibodies or aptamers (see previous posts). We can also inhibit FGFR3 inside the cell. In the last decade, a large class of drugs which block the receptor enzymes’ activation inside the cells has emerged resulting from the increased knowledge of the cell machinery, the tyrosine kinase inhibitors (TKI).
Tyrosine kinase inhibitors
Several TKIs are already being used in the treatment of many types of cancers. They work by hindering the phenomenon that starts the signaling cascade of the receptor enzyme after an activator binds to it, outside the cell. Taking FGFR3 as an example, we have already reviewed this: FGFR3 is turned on when an activator (a ligand, a FGF) binds to the extracellular domain of the receptor. The receptor attracts another FGFR3 and they form a couple (a dimmer).
The dimmer turns its conjugated body, causing the exposure of the so called Adenosine TriPhosphate (ATP) pockets in the intracellular parts of both receptors, which are like electric plugs. These electric plugs attract the ATP molecules. Think about ATPs like batteries capable of transferring energy through cables in a car. In the case of ATPs, this energy transfers are made by charged atoms (ions) dislocation. The arrival and binding of the ATP charged phosphates to the ATP pockets, we call this phosphorylation, will attract other nearby proteins, one after another, producing the cascade of chemical reactions which in the end will stimulate the cell nucleus to produce new proteins or inhibit the production of others, or will stimulate or block the ability of the cell to multiply.
The event described here is not exclusive of FGFR3: the other FGFRs and many other receptor enzymes do the same to transmit their signal to the nucleus. This is an important concept because represents one of the major challenges to find the right TKI blocker for FGFR3. This link will take you to an animation showing the signaling cascade of epidermal growth factor receptor (EFGR), which is a receptor enzyme which works in a similar way FGFR3 does (you will need to watch only the first two minutes of the animation).
TKIs are small molecules designed to bind to and ´close´ the ATP pockets in the intracellular domains of the receptor enzymes. They work like those covers we use to protect children from electric shocks (figure).
Before we continue, I invite you to follow this link, which will take you to an animation showing the mechanism of action of lapatinib, a TKI designed to block EGFR. You must be aware that this is for learning purposes only, it is not intended to promote the drug anyway.
The idea is simple: with those ATP pockets closed, ATPs cannot deliver phosphates and the signaling cascade doesn´t start. It looks like an attractive solution. The TKIs molecules are small and are effective, so where is the issue?
The ATP pockets share great homology (have similar structures) across the majority of the receptor enzymes, so the chance is great that a particular TKI will block several distinct enzymes from different families. This is the reality. There is already a good number of FGFR inhibitors developed (see short and partial list below). You see that I didn´t put a number after the acronym. This means that it is very likely that a TKI designed to block one of the FGFRs will block all the others, too, as they are very similar. In fact, the first TKIs ever developed block a large number of distinct enzymes. More recent ones are more specific, with the improvement of the understanding of the chemical interactions among the molecules and also with the release of more sophisticated drug design computer programs.
Some of the available anti-FGFR TKIs:
- TKI258 (dovitinib)
One question which will naturally occur to one thinking in the therapy for ACH is: do TKIs reach the growth plate? The answer is yes. For instance, tests made with PD176067 showed enlargement in both the proliferative and hypertrophic zones of the growth plate, an effect that was assumed as a reaction to the compound.The TKIs listed in the table block FGFR3, but block also the other FGFRs and/or enzymes from the PDGFR (platelet derived growth factor receptor) and VEGFR (vascular endothelial growth factor receptor) families, too. This link takes you to a recent technical review in FGFR inhibition in cancer..
Recently, two new FGFR3 inhibitors, NF449 and A31 have been described and show more specific properties. If the pre-clinical experiments keep bringing promising results, molecules like A31 could reach clinical trials in three to five years.
TKIs have a number of clear positive characteristics:
- They are small
- They reach the growth plate
- They can be given through the mouth
- They are becoming more and more specific (in ACH, they have to be)
In the next post, we will continue our journey inside the chondrocyte. We still have other options in terms of blocking FGFR3 signaling.