{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:53:36Z","timestamp":1790855616785,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,7,24]],"date-time":"2009-07-24T00:00:00Z","timestamp":1248393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2009,9,16]],"date-time":"2009-09-16T00:00:00Z","timestamp":1253059200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2010,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant tumors, the most common being Malignant Peripheral Nerve Sheath Tumor (MPNST). NF1\u2010MPNST 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\u2010targeted therapies. Recently, the\n                    <jats:italic>NF1<\/jats:italic>\n                    gene product, neurofibromin, was shown to negatively regulate the phosphoinositide\u20103\u2010kinase (PI3K)\/Protein Kinase\u2010B (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\u2010MPNST explant grown subcutaneously in NOD\u2010SCID mice, to evaluate the effect of the mTOR inhibitor rapamycin. We demonstrate that rapamycin significantly inhibited human NF1\u2010MPNST mTOR pathway activation and explant growth\n                    <jats:italic>in vivo<\/jats:italic>\n                    at doses as low as 1.0 mg\/kg\/day, without systemic toxicities. While rapamycin was effective at reducing NF1\u2010MPNST 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\u2010associated, and likely sporadic, MPNSTs.\n                  <\/jats:p>","DOI":"10.1002\/ijc.24783","type":"journal-article","created":{"date-parts":[[2009,7,24]],"date-time":"2009-07-24T14:48:42Z","timestamp":1248446922000},"page":"563-571","source":"Crossref","is-referenced-by-count":40,"title":["Preclinical\n                    <i>in vivo<\/i>\n                    evaluation of rapamycin in human malignant peripheral nerve sheath explant 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