Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant
tumors, the most common being
Malignant Peripheral Nerve Sheath Tumor (
MPNST). NF1-MPNST patients have an overall poor survival due to systemic
metastasis. Currently, the management of MPNSTs includes surgery and radiation; however, conventional
chemotherapy is not very effective, underscoring the need for effective biologically-targeted
therapies. Recently, the NF1 gene product,
neurofibromin, was shown to negatively regulate the phosphoinositide-3-kinase (PI3K)/
Protein Kinase-B (Akt)/
mammalian Target Of Rapamycin (mTOR) pathway, with loss of
neurofibromin expression in established human
MPNST cell lines associated with high levels of mTOR activity. We developed and characterized a human NF1-MPNST explant grown subcutaneously in NOD-SCID mice, to evaluate the effect of the mTOR inhibitor
rapamycin. We demonstrate that
rapamycin significantly inhibited human NF1-MPNST mTOR pathway activation and explant growth in vivo at doses as low as 1.0 mg/kg/day, without systemic toxicities. While
rapamycin was effective at reducing NF1-MPNST proliferation and angiogenesis, with decreased CyclinD1 and
VEGF respectively, there was no increase in
tumor apoptosis.
Rapamycin effectively decreased activation of S6 downstream of mTOR, but there was accompanied increased Akt activation. This study demonstrates the therapeutic potential and limitations of
rapamycin in NF1-associated, and likely sporadic, MPNSTs.