Targeting mTOR signaling for cancer therapy

Huang, Shile; Houghton, Peter J.

doi:10.1016/s1471-4892(03)00071-7

Cited by 408 publications

(276 citation statements)

References 45 publications

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“…and 4E-BP1, as well as on different compensatory mechanisms which link PI3K/mTOR and MAPK signaling (18,20). Our results demonstrate that prodiginines target mTOR pathway.…”

Section: Discussionmentioning

confidence: 63%

“…Interest in identifying and developing new mTOR inhibitors has increased since the second generation of mTOR inhibitors showed encouraging results in the treatment of different types of cancer, including melanoma (18). Melanoma is an extremely aggressive disease with high metastatic potential and notoriously strong resistance to cytotoxic agents.…”

Section: Introductionmentioning

confidence: 99%

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Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and Obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modelling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.3

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“…and 4E-BP1, as well as on different compensatory mechanisms which link PI3K/mTOR and MAPK signaling (18,20). Our results demonstrate that prodiginines target mTOR pathway.…”

Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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“…In particular, mTOR is regarded as an essential molecule in maintaining the transformed phenotype and therefore in regulating the sensitivity of cancer cells to mTOR inhibitors (Bjornsti and Houghton, 2004). Rapamycin and its derivatives, such as CCI-779, RAD001 and AP23573, specifically bind to the intracellular FKBP12 protein to form a drug-receptor complex that then interacts with and suppresses mTOR, resulting in inactivation of its downstream molecule p70S6 kinase (p70S6K) (Huang and Houghton, 2003;Sawyers, 2003). Accumulating results from phase I and II trials suggest that the inhibition of mTOR signaling could be exploited as a cancer-specific therapy (Peralba et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

et al. 2006

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The mammalian target of rapamycin (mTOR) plays a central role in regulating the proliferation of malignant glioma cells, and mTOR-specific inhibitors such as rapamycin analogs are considered as promising therapy for malignant gliomas. However, the efficacy of mTOR inhibitors alone in the treatment of patients with malignant gliomas is only modest, potentially because these agents rather than acting as mTOR kinase inhibitors instead interfere with the function of only mTOR/raptor (regulatory-associated protein of mTOR) complex and thus do not perturb all mTOR functions. The purpose of this study was to determine whether global inhibition of the mTOR molecule enhances the antitumor effect of rapamycin on malignant glioma cells. We showed that rapamycin induced autophagy and that inhibition of autophagy by small interfering RNA (siRNA) directed against autophagyrelated gene Beclin 1 attenuated the cytotoxicity of rapamycin in rapamycin-sensitive tumor cells, indicating that the autophagy was a primary mediator of rapamycin's antitumor effect rather than a protective response. Exogenous expression of an mTOR mutant interfering with its kinase activity markedly enhanced the incidence of rapamycin-induced autophagy. Moreover, silencing of mTOR with siRNA augmented the inhibitory effect of rapamycin on tumor cell viability by stimulating autophagy. Importantly, not only rapamycin-sensitive malignant glioma cells with PTEN mutations but also rapamycin-resistant malignant glioma cells with wild-type PTEN were sensitized to rapamycin by mTOR siRNA. These results indicate that rapamycin-induced autophagy is one of the agent's antitumor effects and that silencing or inhibiting mTOR kinase activity could enhance the effectiveness of rapamycin.

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“…In addition, 2 preclinical studies reported the inhibition of growth of PTEN-mutant tumor cells by CCI-779, both in vitro and in the PTEN ± mouse model [9][10][11]. Clinical studies in patients with other solid tumors demonstrated that CCI-779 was well tolerated, with the major adverse events being myelosuppression, cutaneous toxicity, nausea/vomiting, diarrhea, and hypertriglyceridemia [6,12]. The dose of 250 mg once weekly as a flat dosing schedule was selected for further study based on therapeutically achieved drug levels.…”

Section: Introductionmentioning

confidence: 99%

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs

et al. 2004

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SummaryObjectives: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs. Study design: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria. Results: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs. Conclusions: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

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Targeting mTOR signaling for cancer therapy

Cited by 408 publications

References 45 publications

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs

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