Researchers suggest the cancer medication sunitinib may be an effective treatment for FSHD.
Study leader Dr. Robert Knight - of the Craniofacial Development and Stem Cell Biology Division at King's College London's Dental Institute in the United Kingdom - and colleagues suggest the cancer drug sunitinib may improve muscle weakness in patients with facioscapulohumeral dystrophy (FSHD).
The researchers recently published their findings in the journal eLife.
FSHD is a form of muscular dystrophy characterized by muscle weakness and wasting, most commonly in the face, shoulders, and upper arms, though it can also affect the pelvis, hips, and lower legs.
Onset of FSHD usually occurs in adolescence. Early symptoms may include a curved spine, "winged" shoulder blades, and the inability to fully close the eyes, whistle, or sip through a straw. Patients may also experience hearing loss, a burning pain in muscles, and chronic fatigue.
Estimates suggest that 1 in 20,000 people in the United States have FSHD, with around 95 percent of cases accounted for by FSHD1 - caused by the shortening of D4Z4 regions of DNA on chromosome 4.
At present, there are no medications that can improve muscle strength in patients with FSHD, only drugs that can increase muscle mass. However, Dr. Knight and team believe sunitinib could be a possible candidate for the former.
Sunitinib and FSHD
Sunitinib is a medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of renal cell carcinoma - a form of kidney cancer - and gastrointestinal stromal tumors (GISTs), tumors of the stomach, intestine, or bowel.
The drug works by blocking receptor tyrosine kinase (RTK), which is a type of chemical messenger that instructs cancer cells to grow.
In their study, Dr. Knight and team note that a type of RTK - rearranged during transfection (RET) - is upregulated in muscle-forming stem cells, or myoblasts, that express a protein called DUX4. This protein is encoded by the DUX4 gene, situated in the D4Z4 region involved in FSHD.
In FSHD, the D4Z4 region is hypomethylated, meaning there is a reduction in the number of methyl groups needed to "silence" genes, including DUX4. This increases DUX4 activity, which is believed to trigger activity in other genes that damage muscle cells.
With this information in mind, the researchers hypothesized that by using sunitinib to block RTK in muscle cells, they could inhibit RET activity and decrease DUX4 expression, which might reduce muscle cell damage.
Sunitinib suppressed RET signaling to reduce muscle cell damage
To test their theory, the team first overexpressed DUX4 in myoblasts from mice. This led to an upregulation of RET, which the team says indicates that RET plays a role in FSHD. Overexpressing DUX4 in human myoblasts produced the same outcome.
Next, the researchers applied sunitinib to DUX4-expressing myoblasts from mice, as well as from DUX4-expressing myoblasts taken from patients with FSHD.
The researchers found that the cancer drug suppressed RET activity in both rodent and human myoblasts, reducing DUX4 expression and decreasing muscle cell damage.
"Specifically, blocking DUX4-mediated RET signaling increases myogenic differentiation, giving further insight into the molecular pathology of DUX4 and highlighting RET signaling as potential drug target," the authors explain.
Overall, Dr. Knight and colleagues say their findings suggest sunitinib may be effective for improving muscle strength in patients with FSHD.
Since the drug is already approved for the treatment of cancer, its safety has already been established, meaning approval for sunitinib as a treatment for FSHD may be well within sight.
"Muscle dystrophies are an untreatable collection of diseases that result in progressive loss of mobility and often premature death, and affect millions of people worldwide.
The discovery that an approved anticancer treatment may prove useful for enhancing the ability of stem cells to repair muscle in a type of muscle dystrophy affecting face and shoulder muscles offers a new route for putative therapies for many patients."
Dr. Robert Knight
The researchers now plan to investigate how sunitinib might improve the muscle-forming ability of myoblasts taken from patients with FSHD.