Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies

Mita, Monica; Mita, Alain C.; Chu, Quincy S.; Rowinsky, Eric K.; Fetterly, Gerald J.; Goldston, M.; Patnaik, Amita; Mathews, Lesley; Ricart, Alejandro D.; Mays, Theresa A.; Knowles, Heather; Rivera, Victor M.; Kreisberg, Jeff; Bedrosian, Camille L.; Tolcher, Anthony W.

doi:10.1200/jco.2007.12.0345

Cited by 256 publications

(177 citation statements)

References 18 publications

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“…Bioconversions of CCI-779 into sirolimus appear to be less than dose proportional, suggesting a saturation of the CYP3A4 capacity at higher dosing . In addition, exposure to deferolimus appears to be less than dose proportional (Mita et al, 2008). As both CCI-779 and sirolimus display similar effects on mTORC1, the respective roles of the parental drug and its main metabolite sirolimus on the overall activity of temsirolimus in renal cancer remain unknown.…”

Section: Pharmacokinetic Limitations Of Rapaloguesmentioning

confidence: 99%

“…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%

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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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Section: Pharmacokinetic Limitations Of Rapaloguesmentioning

confidence: 99%

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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“…At the top of the list is the mTOR pathway where three Food and Drug Administration (FDA)-approved inhibitors are currently available, such as rapamycin, everolimus, and temsirolimus, with more in development, including the recently described deforolimus (Cohen, 2008). Inhibitors of mTOR have already been investigated in lung cancer, with clear evidence of anticancer activity both as single agents and in combination with cytotoxic chemotherapy and radiation (Milton et al, 2007;Sarkaria et al, 2007;Mita et al, 2008). Interestingly, a recent report in the New England Journal of Medicine documented a striking therapeutic effect of mTOR-targeted therapy by sirolimus to angiomyolipomas, which are lesions attributable to TSC dysfunction in patients with TS (Bissler et al, 2008).…”

Section: Mtor and Kras In The Clinicmentioning

confidence: 99%

Role of LKB1 in lung cancer development

Makowski

Hayes

2008

Br J Cancer

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“…Ridaforolimus was initially evaluated in 2 phase 1 clinical trials in patients with relapsed or refractory solid tumors (9,10). On the basis of preliminary evidence of clinical activity, as well as additional mechanistic considerations, endometrial cancer and sarcoma have emerged as promising indications for treatment with ridaforolimus.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Ridaforolimus and Potential Cell-Cycle Determinants of Sensitivity in Sarcoma and Endometrial Cancer Models

Squillace

Miller

Cookson

et al. 2011

Molecular Cancer Therapeutics

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Ridaforolimus is a nonprodrug rapamycin analogue that potently inhibits mTOR and has shown significant activity in patients with metastatic sarcoma and endometrial cancer, two diseases where high unmet need remains. Here, we evaluated the activity of ridaforolimus in preclinical models of these tumor types and used these models to explore molecular correlates of sensitivity. The in vitro sensitivity of a panel of sarcoma and endometrial cancer cell lines was established by measuring the effect of ridaforolimus on cell proliferation rate, revealing broad inhibition at low nanomolar concentrations. Additional benefit was found when ridaforolimus was combined with agents used to treat sarcoma and endometrial cancer patients. In vivo, potent antitumor activity of ridaforolimus associated with inhibition of mTOR signaling was observed in sarcoma and endometrial xenograft models. Immunoblot analysis was conducted to assess the expression and activation state of multiple signaling proteins in the phosphoinositide-3-kinase/AKT/mTOR and cell-cycle pathways. In endometrial but not sarcoma cell lines, the absence of PTEN or elevated levels of phosphorylated or total AKT was associated with greater sensitivity. However, in both tumor types, the proportion of cells in the G 0 -G 1 phase before treatment correlated significantly with ridaforolimus sensitivity. Consistent with this, expression of several G 1 phase cell-cycle proteins, notably p21 and p27, was higher in more sensitive lines. These results underscore the promise of ridaforolimus as a single agent or combination treatment of these tumor types and suggest novel potential predictive biomarkers of sensitivity to an mTOR inhibitor based on cell-cycle status. Mol Cancer Ther; 10(10); 1959-68. Ó2011 AACR.

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Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies

Cited by 256 publications

References 18 publications

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

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

Role of LKB1 in lung cancer development

Antitumor Activity of Ridaforolimus and Potential Cell-Cycle Determinants of Sensitivity in Sarcoma and Endometrial Cancer Models

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