A Single Arm, Multicenter Phase II a Trial of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas That Cannot be Removed by Surgery
Neurofibromatosis 1 (NF1) is an autosomal dominant disease affecting 1 in 3000 to 1 in 4000
people. NF1 is characterized by multiple dermal neurofibromas, plexiform neurofibromas,
malignant peripheral nerve sheath tumors (MPNST), and optic pathway gliomas, as well as by
café-au-lait spots and abnormalities of the skeletal, cardiovascular and central nervous
systems. The NF1 gene is located on chromosome 17q11.2, and its protein, neurofibromin,
functions as a tumor suppressor.
People with NF1 have a decrease in life expectancy of 15 years, with MPNST as a leading
cause of death in young adults. A specific phenotype at risk of mortality has been
identified, patients with subcutaneous neurofibromas. Individuals with subcutaneous
neurofibromas are more than 3 times as likely to have internal plexiform neurofibromas as
others. Individuals with internal plexiform neurofibromas are 18 times more likely to
develop MPNST than patients without internal plexiform neurofibromas. Beside MPNST, internal
plexiform neurofibromas can be life-threatening or cause of significant morbidity through
compression of organs mainly spine or nerve roots.
The conventional treatment of these internal plexiform neurofibromas is surgery. This
surgery can be possible on a single and limited tumor. On the other hand these tumors are
often surgically intractable due to their multiplicity and their infiltrating
characteristics. In this context a medical treatment decreasing the size of these tumors
would have its place with as short term aim to lower the consequence of compression and
long-term aim to reduce the risk of malignant transformation.
NF1 is a consequence of the loss-of-function mutations in the NF1 tumor suppressor gene. The
NF1-encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (RasGAP).
Accordingly, deregulation of Ras is thought to contribute to NF1 development. The mTOR
pathway is tightly regulated by neurofibromin. mTOR is constitutively activated in both
NF1-deficient primary cells and human tumors in the absence of growth factors. This aberrant
activation depends on Ras and PI3 kinase, and is mediated by the phosphorylation and
inactivation of the TSC2-encoded protein tuberin by AKT. Importantly, tumor cell lines
derived from NF1 patients, and a genetically engineered cell system that requires
Nf1-deficiency for transformation, are highly sensitive to the mTOR inhibitor rapamycin.
Furthermore, the activation of endogenous Ras leads to constitutive mTOR signaling in this
disease state, and in normal cells Ras is differentially required for mTOR signaling in
response to various growth factors. Thus, the NF1 tumor suppressor is an indispensable
regulator of TSC2 and mTOR. Ras plays a critical role in the activation of mTOR in both
normal and tumorigenic settings.
mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated
malignancies in a genetically engineered murine model. In these tumors rapamycin does not
function via mechanisms generally assumed to mediate tumor suppression, including inhibition
of HIF-1 alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1.
The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth
19% to 60% after 4 days of treatment in NF1 MPNST cell lines.
Finally, these data suggest that rapamycin, or its derivatives such as everolimus may
represent a viable therapy for NF1. This proof of concept has been done in tuberous
sclerosis where rapamycin was efficient to treat angiomyolipomas11.
The management of neurofibromatoses in France is coordinated by Pr. Pierre WOLKENSTEIN
through the French National Referral Centre for Neurofibromatoses and a network, NF-France.
The cohort followed up by the centre and its network is constituted of about 3000 patients
and among them between 80 and 100 have life-threatening internal plexiform neurofibromas.
Therefore the investigators propose a trial to evaluate the efficacy of everolimus in
surgically intractable and life-threatening internal neurofibromas in neurofibromatosis 1
based on the data of the literature and on our cohort.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Radiographic response assessed by MRI analysis
after 1 year of treatment
Pierre Wolkenstein, MD, PhD
Assistance Publique - Hôpitaux de Paris
France: Ministry of Health