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.Malignant Peripheral Nerve Sheath Tumors (MPNST) have an incidence of 0.001% in the general population, however, as many as 5-10% of individuals with the inherited cancer syndrome, neurofibromatosis type 1 (NF1) will develop an MPNST in their lifetime. In adults with NF1, MPNSTs are the most common malignancy and the major source of morbidity.1 The poor survival associated with NF1-associated MPNST (NF1-MPNST) reflects the earlier age of onset, multiple MPNSTs, and their overall resistance to conventional chemo-and radiation treatment. Unfortunately, pre-or postoperative adjuvant chemotherapy is not effective 2 and the five year survival after MPNST diagnosis is $20% for individuals with NF1.3 In addition, these tumors have a high propensity to metastasize to bone and lung, even after surgical excision and local radiation therapy. 4 As such, there is a recognized need for effective targeted biological therapies for NF1-MPNSTs.With the identification of the NF1 protein (neurofibromin), it became possible to consider treatments that reverse the biochemical abnormalities resulting from loss of neurofibromin function in NF1-MPNST. Neurofibromin functions in part as a Ras GTPase Activating Protein (Ras-GAP) by accelerating the conversion of active, GTP-bound p21-Ras to inactive, GDP-bound Ras and reducing p21-Ras stimulation of cell growth. We and others have previously shown that p21-ras-GTP levels are elevated in human NF1-MPNST tumors. 5,6 However, biological therapies targeting p21-Ras activation, such as farnesyltransferase inhibitors (FTIs), ...

No abstract