Mammalian target of rapamycin inhibitors in sarcomas

Abstract

Clinical benefit response uses standard Response Evaluation Criteria in Solid Tumors of complete response and partial response as well as stable disease lasting at least 4 months as an endpoint. This endpoint has been shown to select promising new agents against sarcomas. Using this endpoint, the use of the mammalian target of rapamycin inhibitor AP23573 has demonstrated activity against sarcomas. The use of the inhibitor RAD001 (everolimus) along with imatinib in patients with imatinib resistant gastrointestinal stromal tumor has shown promise. Future studies will need to be performed to determine the clinical differences among the mammalian target of rapamycin inhibitors in different subsets of sarcomas.

Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors

“…Fluorescence in situ hybridization analysis identified NF1 mutations in some primary sporadic MPNST, but this STS26T cell line does not have NF1 mutations and shows low RAS-GTP and low phosphorylated extracellular signal-regulated kinase (8 -10). This result is important as it implies that mTOR signaling may be relevant to NF1-driven and non -NF1-driven MPNSTs and is consistent with a role for mTOR signaling in other types of sarcomas, and with the finding that NF1-driven and non-NF1 MPNST are indistinguishable by microarray (10,11,29,44). An accurate determination of the percentage of sporadic MPNST cell lines with elevated phospho-S6K will require generation of additional cell lines lacking NF1 mutation.…”

“…Whether rapamycin treatment would be effective only in NF1-derived MPNSTs, or equally effective in sporadic MPNST, is not known. There is also considerable interest in using rapamycin (Serolimus) or the rapamycin derivatives RAD001 (Everolimus) and CCI-779 (Temserolimus) to treat sarcomas (28,29).…”

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

“…Indeed, it has been reported from Phase II studies that a rapamycin analogue shows some beneficial response in 28-30% of advanced sarcomas. 1,14,32 Third, this study showed that mTOR cassette proteins are not activated simultaneously in most tissue sections. Earlier studies also have yielded mixed results: significant association between activation of Akt and mTOR was shown in non-small cell lung carcinoma, 33 but not in glioblastoma.…”

Pediatric sarcomas occurring in adults

“…There are anecdotes of responses of patients to the combination of gemcitabine and docetaxel, and the Sarcoma Alliance for Research through Collaboration (SARC) are examining the combination in a formal phase II study in refractory disease. The mammalian target of rapamycin (mTOR) inhibitor AP23573 has yielded occasional durable partial responses in patients with metastatic disease, raising the hope of combinations of an mTOR inhibitor and either cytotoxic or other targeted agents as novel and effective for recurrent disease [30]. Accordingly, patients with refractory disease are very suitable candidates for investigational therapy.…”