In the last weeks several interesting studies have been
published in the bone
development and fibroblast growth factor receptor 3 (FGFR3) fields. Although most of them are not directly related to achondroplasia,
their results bring new insights and possibilities to those interested in
therapies for FGFR3-related bone dysplasias and other forms of growth
restriction disorders.
This text may seem superficial for the technical reader. I try to avoid using heavy jargon to allow people not familiar with science
language to understand the topics discussed. More technical information can be
found in the references provided.
By the other side, don’t worry about not understanding a
concept or expression used here. Try visiting the blog’s glossary page and the links
provided throughout the text, which will take you to other reviews published here. There you can
find explanations for most of the technical topics. The most important thing here is: never give up learning.
There are six different studies working on five drug classes that I will be reviewing in two parts. In this first one, let's take a look on the studies working with fluazuron and C-type natriuretic peptide (CNP).
Fluazuron, an anti-parasite used to treat tick infestation
in cattle, inhibits FGFR3 and reduces
cancer cell growth in models of bladder cancer (1).
Background
FGFR3 has been identified as an important cancer growth driver (it stimulates cancer cells to proliferate or multiply and to stay alive) in about two
thirds of the cases of bladder cancer and its suppression has been showing to
reduce tumor size (2). Therefore, drugs working against FGFR3 might be useful to treat this
form of cancer.
However, drugs used in the treatment of cancer are very
expensive and the costs have been escalating in the last decade, with the
introduction of targeted therapies (drugs developed to affect a single or a
small number of targets, which helps to reduce toxicity and to improve
efficacy), and this has been considered a relevant restriction to access in
many countries. (3-5).
The study
Having the cost restriction in mind, a Chinese group
explored a list of old approved drugs within the drug repurposing strategy
(6; also reviewed here) to check if there would be any suitable drug that could be used
against FGFR3.
The researchers found that one compound of a list of old drugs approved by FDA,
fluazuron (Figure 1), directly inhibited FGFR3 by blocking its activation site (Figure 2), therefore
also blocking FGFR3-dependent enzymatic cascades (Figure 3), including the mitogen-activated protein kinase (MAPK) (1).
The MAPK pathway is considered key for bone growth (7) and comprises the enzymes RAF, RAS, MEK and ERK (see Figure 3).
The way the researchers described fluazuron's mechanism of action on FGFR3 makes it looks like other tyrosine-kinase inhibitors such as NVP-BGJ398, recently reviewed here.
Figure 1. Fluazuron.
 |
| Fluazuron |
The researchers confirmed that fluazuron was capable of causing significant
reduction of tumor size in an animal model and that its mechanism of action was
related to the suppression of FGFR3 activity. They concluded that fluazuron could be further tested to verify its potential application as a therapy for human bladder cancer.(1)
Figure 2. Prediction of the docking site of fluazuron on FGFR3
 |
| From iview, an interactive WebGL visualizer for protein-ligand complex (from ref.: 1). |
Figure 3. FGFR3 signaling cascades in the chondrocyte.
 |
| Signaling pathways activated by FGF/FGFR. FGFs induce dimerization,
kinase activation and transphosphorylation of tyrosine residues of
FGFRs, leading to activation of downstream signaling pathways. Multiple
pathways are stimulated by FGF/FGFR signaling such as Ras-MAP kinase,
PI-3 kinase/AKT and PLC-γ pathways. Furthermore, FGF signaling can also
stimulate STAT1/p21 pathway. FGF/FGFR signaling also phosphorylates the
Shc and Src protein. FGF/FGFR play crucial roles in the regulation of
proliferation, differentiation and apoptosis of chondrocytes via
downstream signaling pathways. From: Su N et al. Bone Research 2014; 2,: 14003; doi:10.1038/boneres.2014.3. Free access. Reproduced here for educational purposes only. |
Implications
Fluazuron is a well known drug mainly used to treat tick
infestation in cattle. Currently, it is approved for
use as a topical, “pour on” therapy, but can also be given through other routes, including orally. It has been shown to be a long lasting drug in the body after absorbed,
either orally or through the skin, and because of this feature it is
recommended to be used once a year, although the treatment can be repeated if
necessary (8,9).
Fluazuron has already been tested in several animal species
as an oral and parenteral compound, and its pharmacokinetics (PK, the study of how the body deals
with a drug – absorption, metabolism, elimination) and pharmacodynamics (PD,
the study of the effect of the drug in the body) are well characterized.
Its therapeutic dose range has been shown to be safe in the tested animals.
These PK and PD analyses showed that the drug is eliminated very slowly from
the body (8-11).
Therefore, fluazuron seems to be safe in low therapeutic
doses in animals and lasts a long time in the body. It is a small molecule
which shows a broad distribution in tissues including liver, muscle and mainly
fat.
Given the current knowledge about its PK, PD and in the insights provided
by this new study in bladder cancer, I think that testing fluazuron in a model
of achondroplasia is something to be seriously considered.
Can you see the picture? Let’s say it works in a model of
achondroplasia and its safety profile is really fair. An oral, low cost drug
that could be used three or four times a year to rescue bone growth in
achondroplasia…
What do we need? A study (or studies) to confirm if it
reaches the growth plate (Figure 4) and its effects in the mutated FGFR3, what it does in
growth plate chondrocytes (can it rescue cell proliferation and maturation?), and
its effects in bone growth in an appropriate in vivo model.
Other questions are related to safety. For example, does fluazuron affect other enzymes of
the FGFR family or from other enzyme families? Given the similarity of the
active sites of the receptor tyrosine-quinases (RTK, the way researchers call
enzymes like FGFR3; reviewed here), we would need to check if fluazuron is
specific enough against FGFR3.
However, the problem here is that this drug is old; its
patent has expired and would not be profitable compared to a brand new
molecule. It falls in the same situation of meclizine, parathyroid hormone (PTH),
statins, other “older” therapies that might be potential options for the
treatment of achondroplasia, but don’t get enough attention due, at least in
part, to lack of economic interests.
Figure 4. Growth plate.
C-type natriuretic peptide (CNP) rescues bone growth in a
juvenile mice model of glicocorticoid therapy (12).
Background
Glicocorticoids are largely used to treat many
acute and chronic diseases due to their anti-inflammatory and immunosuppressive
effects. Chronic use of steroids in children is known to cause growth
retardation and may lead to adult short stature.
A CNP analogue, vosoritide, is currently being tested in a phase 2 clinical trial in children with achondroplasia. Can CNP revert the growth retardation effect caused by chronic use of glicocorticoids in children?
The study
The pioneer Japanese group from Kyoto that have been exploring the use
of CNP for achondroplasia has just published a new study where they tested
whether the use of CNP in animals exposed to chronic use of glicocorticoids would have
impact in bone growth (12).
Basically, they found that CNP was able to significantly rescue
bone growth in treated animals to an extent close to what was seen in non-treated
animals (controls). Here are their conclusions (copied from the highlights box available at the publisher's website, here):
- CNP restores impaired skeletal growth due to dexamethasone in a murine model.
- CNP restores the decreased hypertrophy of growth plate chondrocytes by dexamethasone.
- CNP could be a therapeutic agent for the glucocorticoid-induced growth retardation.
Implication
This is the first study that I am aware of exploring a new potential
clinical indication for CNP in bone development conditions other than achondroplasia.
Since the use of glicocorticoids to treat chronic inflammatory or autoimmune disorders is quite common
during childhood, and based on these compelling results, it is expected that CNP analogues could be used to counteract
the growth retardation effects of that drug class in those conditions.
This brings us to another aspect of this study, which is the fact that CNP can be used in other conditions regardless of the status of FGFR3.
As a consequence, the potential market for CNP analogues seems to be increasing, which is good for drug developers interested in investing in therapies for bone growth disorders.
Nonetheless, there are other several potential indications also waiting to be included in the CNP's research map, starting with hypochondroplasia and other bone dysplasias dependent of the MAPK pathway (Figure 3), the one which is directly regulated by CNP. We hope they will not be forgotten.
And finally, there will be no surprise about future announcements of clinical studies to confirm that CNP or its analogues can be given to children under chronic glicocorticoid therapy.
For a review of CNP, click here. For a review of vosoritide development, click here.
References
1. Ke K et al. In silico prediction and in vitro and in vivo validation of acaricide fluazuron as a potential inhibitor of FGFR3 and a candidate anticancer drug for bladder carcinoma.
Chem Biol Drug Des 2016. doi: 10.1111/cbdd.12872. [Epub ahead of print]
2. di Martino E et al. A decade of FGF receptor research in bladder cancer: past, present, and future challenges. Adv Urol. 2012;2012:429213. Free access.
4. Goldstein DA et al. Global differences in cancer drug prices: A comparative analysis. J Clin Oncol 34, 2016 (suppl; abstr LBA6500). Presented at 2016 ASCO Annual Meeting. Free access.
5. Lopes Jr. GL et al. Access to cancer medications in low- and middle-income countries. Nat Rev Clin Oncol 2013;10: 314–22.
6. Strittmatter SM. Overcoming Drug Development Bottlenecks With Repurposing: Old drugs learn new tricks. Nat Med 2014; 20 (6):590-1. Free access.
7. Ornitz DM and Marie JP. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev 2015; 29:1463–86. Free access.
8. European Medicines Agency. Veterinary Medicines and Inspections. Committee for Medicinal Products for Veterinary Use. FLUAZURON. Summary report (2). EMEA/CVMP/126892/2006-FINAL. April 2006. Available online at: http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500014284.pdf. Free access.
9. FAO/UN. Residues of some veterinary drugs in foods and animals 1997. Fluazuron. Available online at: http://www.fao.org/fileadmin/user_upload/vetdrug/docs/41-10-fluazuron.pdf. Free access.
10. Gomes LVC et al. Acaricidal effects of fluazuron (2.5 mg/kg) and a combination of
fluazuron
(1.6 mg/kg) + ivermectin (0.63 mg/kg), administered at different
routes, against Rhipicephalus (Boophilus) microplus parasitizing cattle.
Experiment Parasitol 2015;153:22–8.
11. Pasay C et al. An exploratory study to assess the activity of the acarine growth inhibitor, fluazuron, against Sarcoptes scabei infestation in pigs. Parasit Vectors 2012;5:40. Free access.
12. Ueda Y et al. C-type natriuretic peptide restores impaired skeletal growth in a murine model of glucocorticoid-induced growth retardation. Bone. 2016 Nov;92:157-167. doi: 10.1016/j.bone.2016.08.026.
