Segmental Overgrowth Syndrome Clinical Trial
Official title:
Open Label Phase II Study of Everolimus (RAD001) in Patients With Segmental Overgrowth Syndrome
This is an open-label, multicenter, single-arm, phase II clinical trial of Everolimus (RAD001) in patients with segmental overgrowth syndrome.
Segmental overgrowth syndromes are very rare diseases with an extremely relevant genetic
background. In some of them, only about 200 cases are known worldwide, such as for example
the Proteus syndrome which presents with asymmetric and fast growth of extremities. Further
overgrowth diseases are the SOLAMEN and the CLOVE syndrome with lipomatosis, vascular
malformations and epidermal nevus as well as the Cowden syndrome with multiple hamartomas and
the Bannayan-Riley-Ruvalcaba syndrome with lipomatosis and macrocephalus. The patients with
overgrowth syndromes all show close clinical overlap. For several years, clinical criteria
(phenotype) for diagnosis and discrimination of these syndromes have been defined.
Results of genetic research can today help to diagnose most of the segmental overgrowth
syndromes which means they can clearly be named. Genes of the PI3K/AKT/PTEN/mTOR signalling
pathway have been identified to be causative for some of these syndromes. PTEN germline
mutations have been known to be present in SOLAMEN, Cowden and Ruvalcaba syndrome patients
all showing tissue overgrowth and close clinical overlap. However, very rarely, somatic PTEN
mutations could be detected in surgical specimen of lipomas or hamartomas of other segmental
overgrowth patients. Only recently, recurrent somatic activating mutations of AKT1 have been
identified in overgrowth tissue of Proteus syndrome patients. Because AKT1 is also activated
by loss-of-function mutations in PTEN, patients with syndromes harbouring germline PTEN
mutations (SOLAMEN, Cowden and Ruvalcaba) and Proteus syndrome patients with activating
mutations of AKT1 show close overlap in clinical manifestations. Furthermore, somatic PI3KCA
mutations have been described to be responsible for the CLOVE syndrome, again a
phenotypically closely related variant of the other overgrowth syndromes. These genetic
results confirmed that patients with overgrowth all share a common feature involving the
PI3K/AKT/PTEN/mTOR signal pathway.
Next to surgical approaches in functional handicapped patients, a standard medical therapy is
not available. Therefore, in most cases, a watch-and-wait strategy is followed. Taking into
account the genetic background of segmental overgrowth patients, mTOR is a promising target
for a possible medical treatment. For example, because the direct molecular consequence of
PTEN loss-of-function is an aberrant activation of the mTOR pathway, targeting mTOR holds the
promise of a causative treatment in PTEN-positive segmental overgrowth patients.
Until today, three case reports have described the successful use of the mTOR inhibitor
Rapamycin for the therapy of patients with segmental overgrowth and PTEN germline mutation.
The Investigator recently started with "off label" use of Rapamycin in these patients. First
results with successfully treated patients have been presented at The Annual meeting of the
German Society of Human Genetics in 2011 and the meeting of the International Society on the
Studies of Vascular Anomalies in 2012. In one patient with segmental overgrowth syndrome and
response to Rapamycin, the investigators could identify a PI3KCA mutation in one lesion. This
case is currently prepared for publication. Interestingly, response on mTOR inhibition could
be demonstrated in some patients although lack of mutation in the published genes responsible
for overgrowth syndromes.
A clinical trial sponsored by the National Cancer Institute tested the ability of Rapamycin
to decrease the activity of proteins that are regulated by mTOR in both benign and cancerous
tumour tissue in Cowden syndrome patients (NCT00971789). Only patients over the age of 18
years were included and multiple biopsies were performed before starting treatment and during
therapy with Rapamycin.
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