The Biology Behind mTOR Inhibition in Sarcoma

Abstract

LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Discuss the function of the mTOR pathway in cancer cell growth and survival.2. Describe the potential mechanism of targeting this pathway by rapamycin and its derivatives for cancer therapy. This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT

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.…”

“…Instead, other growth factor receptors have been implicated in pathology of bone and soft tissue tumors, including insulin-like growth factor receptor and fibroblast growth factor receptor. 1 Regardless of the particular growth factor receptor pathway involved, mTOR inhibitors may be effective in the cases exhibiting mTOR activation as far as mTOR cassette is activated even in the defined subsets. Indeed, it has been reported from Phase II studies that a rapamycin analogue shows some beneficial response in 28-30% of advanced sarcomas.…”

“…[1][2][3] Recently, novel approaches targeting the underlying specific molecular events have been developed for a defined subset of bone and soft tissue tumors.…”

“…18,19 Recent preclinical evidence supports the efficiency of mTOR inhibitors in the treatment of sarcomas: rapamycin treatment resulted in reduced phosphorylation of proteins functioning downstream of mTOR and can greatly reduce the growth of cell lines from rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma. 1,2,19,20 Thus, rapamycin could be a powerful therapeutic regimen in the treatment of bone and soft tissue tumors, especially if the mTOR pathway is shown to be a critical effector of growth signaling not only from EGFR, but from other growth factor receptors as well. However, the overexpression or activation of mTOR and its association with biological behavior as well as intracellular signaling cascade related to EGFR in this tumor group have not been described in detail.…”

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

“…mTOR, a Expression of IGF2 in mesenchymal neoplasms SE Steigen et al major downstream effector of the IGF signaling pathway, is targeted by a new generation of rapamycin analogs, which are undergoing active evaluation in clinical trials. 54 For GISTs in particular, a study on inhibiting IGF1R has shown promising results. 55 In summary, following a broad examination of mesenchymal tumors by immunohistochemistry on tissue microarrays, expression of the growth factor and therapeutic target IGF2 is shown in solitary fibrous tumors, synovial sarcomas, myxoid liposarcomas, GISTs, malignant peripheral nerve sheath tumors, chondrosarcomas, undifferentiated pleomorphic sarcomas (MFH), Ewing's sarcomas and in tenosynovial giant cell tumors.…”