Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data

Tanaka, Chiaki; O’Reilly, Terence; Kovarik, John M.; Shand, N.; Hazell, Katharine; Judson, Ian; Raymond, Éric; Zumstein-Mecker, Sabine; Stephan, Christine; Boulay, Anne; Hattenberger, Marc; Thomas, George; Lane, Heidi A.

doi:10.1200/jco.2007.14.1127

Cited by 199 publications

(138 citation statements)

References 23 publications

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“…This assumption has had huge clinical implications as phospho-S6 or phospho-S6K1 is often utilized in rapamycin-based clinical studies to measure in vivo inhibition of mTORC1. 26,27 In contrast to these assumptions, we recently reported that rapamycin differentially regulated S6Ks versus 4E-BP1. 4 While rapamycin inhibited S6K1 in all cell lines that were tested, the phosphorylation of 4E-BP1 was differentially controlled relative to the cell type.…”

Section: Differential Regulation Of S6ks Versus 4e-bp1mentioning

confidence: 83%

Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy

Choo¹,

Blenis²

2009

Cell Cycle

197

146

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The mTORC1 signaling pathway is a critical regulator of cell growth and is hyper activated in many different cancers. Rapamycin, an allosteric inhibitor of mTORC1, has been approved for treatment against renal cell carcinomas and is being evaluated for other cancers. Mechanistically, mTORC1 controls cell growth in part through its two well-characterized substrates S6K1 and 4E-BP1. In this review, we discuss the implications of a recent finding that showed differential inhibition of S6K1 and 4E-BP1 by rapamycin, leading to cell-type-specific repression of cap-dependent translation. We discuss potential mechanisms for this effect, and propose that mTOR-specific kinase inhibitors, instead of rapamycin, should be considered for mTOR-targeted cancer therapy.

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Section: Differential Regulation Of S6ks Versus 4e-bp1mentioning

confidence: 83%

Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy

Choo¹,

Blenis²

2009

Cell Cycle

197

146

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“…The selection of 30 mg per week as the dosage for everolimus was based on the results of a phase I study in which single doses of everolimus of up to 30 mg had been shown to be satisfactorily safe and capable of inhibiting a biomarker indicative of target activity (S6K1 activity in peripheral blood mononuclear cells) (O'Donnell et al, 2008). Furthermore, based on the assumption that to be efficacious, the drug should achieve target inhibition that is at least as great as that associated with efficacy in the rat model (Tanaka et al, 2008), and accepting the modelling assumption of a similar pharmacokinetic -pharmaco- …”

Section: Discussionmentioning

confidence: 99%

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

et al. 2009

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Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m À2 on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33 -69) were entered; 11 had prior taxane therapy for breast (n ¼ 5), ovarian (n ¼ 3), and vaginal cancer (n ¼ 1) or angiosarcoma (n ¼ 2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m À2 , warranting further clinical investigation.

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“…Surprisingly, the effects of rapalogues on the levels of cholesterol and triglyceride were never fully considered to monitor the biological effects of rapalogues in trials in patients with cancer. As easily available cells were peripheral blood mononuclear cells (PBMCs), most studies were carried out looking at the phosphorylation of S6K and 4EBP1 in those cells (Hidalgo et al, 2006;Mita et al, 2008;O'Donnell et al, 2008;Tanaka et al, 2008). Those data consistently showed a dose-dependent effect of rapalogues in inducing a dephosphorylation of S6K and/or 4EBP1 in PBMC.…”

Section: Usefulness Of Surrogate Markers and Imaging To Monitor The Ementioning

confidence: 99%

“…Those data consistently showed a dose-dependent effect of rapalogues in inducing a dephosphorylation of S6K and/or 4EBP1 in PBMC. In a recent study, we showed that modelling the S6K dephosphorylation in PBMC in animals and humans under exposure to everolimus allows prediction of a threshold level of activity of this drug in humans and helps select dosing for phase II studies (Tanaka et al, 2008). Similarly, another study addressed the direct effects of everolimus on phosphorylation of several kinases including S6K and AKT in skin and tumour tissue biopsies (Tabernero et al, 2008).…”

Section: Usefulness Of Surrogate Markers and Imaging To Monitor The Ementioning

confidence: 99%

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

et al. 2008

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The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1a-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

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Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data

Abstract: A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.

Cited by 199 publications

References 23 publications

Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy

Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

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