An overview of the mTOR pathway as a target in cancer therapy
ABSTRACT 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.
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Article: Too much or too littleCell cycle (Georgetown, Tex.) 09/2012; 11(17):3147-8. DOI:10.4161/cc.21588 · 4.57 Impact Factor
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ABSTRACT: Objective: 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. Results: 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. Conclusions: 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.Cancer Chemotherapy and Pharmacology 09/2012; 70(6). DOI:10.1007/s00280-012-1968-x · 2.77 Impact Factor
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ABSTRACT: Background Myelodysplastic syndrome (MDS) continues to extract major morbidity and mortality, thus, novel treatments are needed. The mTOR inhibitor, RAD001, inhibits cellular pathways important to MYC protein stability and cell growth. Pharmacodynamic biomarkers could be useful in distinguishing between disease resistance that occurs even though mTOR is successfully inhibited, suggesting a need for a different treatment strategy, versus resistance that might respond to changes in drug dosage or schedule. Patients and Methods We conducted a small Phase 2 trial of RAD001 in patients with low and intermediate-1 risk MDS (n=7). Protein S6K1 (S6) is downstream of mTOR while AKT is upstream of mTOR. Therefore, to evaluate the pharmacodynamic effects of RAD001, S6 and AKT phosphorylation (pS6, pAKT) were measured by peripheral blood flow cytometry. Results Sequential weeks of RAD001 produced a decrease in pS6, while pAKT was maintained or increased. There were no clinical responses despite the biomarker evidence of intended pharmacodynamic effect. Conclusions The pS6/pAKT ratio could be useful as a biomarker of target inhibition byRAD001 (clinicaltrials.gov identifier: NCT00809185).Clinical lymphoma, myeloma & leukemia 11/2013; 14(2). DOI:10.1016/j.clml.2013.10.001 · 2.02 Impact Factor