An overview of the mTOR pathway as a target in cancer therapy
Northwestern University, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center , 303 East Superior Street, Lurie 3-107, Chicago, IL 60611 , USA +1 312 5034267 Expert Opinion on Therapeutic Targets
(Impact Factor: 5.14).
04/2012; 16(5). DOI: 10.1517/14728222.2012.677439
Introduction: The mammalian target of rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of mRNA translation in mammalian cells. The mTOR inhibitor rapamycin and its derivatives have shown potent antineoplastic activities in many preclinical models and clinical trials. First-generation mTOR inhibitors are now FDA-approved for the treatment of renal cell carcinoma. Areas covered: This article reviews the components of the mTOR pathway and their normal functions, highlighting the most common alterations in the pathway, seen in various human malignancies. It also discusses elements and effectors of this signaling cascade and reviews the therapeutic relevance of pharmacological inhibitors of the pathway in several malignancies, including lymphomas, leukemias, sarcomas, renal cell carcinoma, and breast cancer. Expert opinion: mTOR targeting is a highly promising therapeutic approach. First-generation mTOR inhibitors have already shown substantial activity in the treatment of certain tumors, while the emergence of second-generation catalytic mTOR inhibitors provides a better approach to target the pathway in malignant cells and has raised the potential for better clinical outcomes in the future.
Available from: Richard B Pearson
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Chondrosarcomas (CS) represent a heterogeneous group of rare sarcomas, poorly responsive to chemotherapy or radiotherapy. When local therapies in recurrent or metastatic disease are exhausted, chemotherapy plays a marginal role. Different molecular pathways have been shown to be activated in CS. In this retrospective study, we summarize our experience in treating a cohort of patients with recurrent unresectable CS with a combination of sirolimus (SIR) and cyclophosphamide (CTX).
Patients and methods:
Ten consecutive patients with unresectable CS were offered off-label treatment with SIR and CTX between 2007 and 2012. Tumor response, progression-free survival (PFS), adverse events, and other relevant clinical data were analyzed.
The median patients' age was 49 (range 28-68). Median disease-free interval since the primary diagnosis was 22.5 months. Median time from the disease recurrence to initiation of SIR and CTX treatment was 21.7 months due to additional local surgical treatments, excision of metastases, or slow asymptomatic progression. One (10 %) objective response was observed, and six (60 %) patients had stabilization of disease for at least 6 months. Three patients had progressive disease. Median PFS was 13.4 months (range 3-30.3). No significant adverse events were observed.
Although advanced CS remains an incurable disease, our experience suggests that a combination of SIR and CTX is well tolerated and may have meaningful clinical activity with disease control rate of 70 %. Further prospective studies are warranted.
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ABSTRACT: The target of rapamycin (TOR) pathway is highly conserved among eukaryotes and has evolved to couple nutrient sensing to cellular growth. TOR is found in two distinct signaling complexes in cells, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). These complexes are differentially regulated and act as effectors for the generation of signals that drive diverse cellular processes such as growth, proliferation, protein synthesis, rearrangement of the cytoskeleton, autophagy, metabolism and survival. Mammalian TOR (mTOR) is very important for development in embryos, while in adult organisms it is linked to aging and lifespan effects. In humans, the mTOR pathway is implicated in the tumorigenesis of multiple cancer types and its deregulation is associated with familial cancer syndromes. Because of its high biological relevance, different therapeutic strategies have been developed to target this signaling cascade, resulting in the emergence of unique pharmacological inhibitors that are either already approved for use in clinical oncology or currently under preclinical or clinical development. Multimodal treatment strategies that simultaneously target multiple nodes of the pathway and/or negative feedback regulatory loops may ultimately provide the best therapeutic advantage in targeting this pathway for the treatment of malignancies.Oncogene advance online publication, 17 December 2012; doi:10.1038/onc.2012.567.
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