Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines

Aissat, Nasredine; Tourneau, Christophe Le; Ghoul, Aïda; Serova, Maria; Bièche, Ivan; Lokiec, François; Raymond, Éric; Faivre, Sandrine

doi:10.1007/s00280-007-0609-2

Cited by 91 publications

(68 citation statements)

References 25 publications

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“…In light of the cell-cycle relationship we uncovered, this may account for why more potent synergistic effects were not observed. Similar combinatorial benefit has been reported for rapamycin with these same cytotoxic agents in breast, hepatocellular carcinoma, and head and neck cancer lines (34)(35)(36).…”

Section: Discussionsupporting

confidence: 73%

“…The mTOR inhibitor rapamycin has been shown to potentiate the cytotoxic activity of multiple chemotherapeutic agents in a number of cancer cell types in vitro (25,34,35). Therefore, an important objective of this study was to determine whether ridaforolimus enhanced the efficacy of chemotherapeutics commonly used in sarcoma and endometrial cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

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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“…In tumours addicted to this growth factor stimulation, chemotherapy combined with mTOR inhibition has shown synergistic anti-tumour effects. For example, data have shown that rapamycin and everolimus can enhance the antitumour activity of paclitaxel (O'Reilly et al, 2003;Mondesire et al, 2004;Faried et al, 2006;Aissat et al, 2007;Haritunians et al, 2007) in a manner related in occurrence and extent to the tumour, dose, and interestingly, the sequence of administration of the mTOR inhibitor and paclitaxel (O'Reilly et al, 2003;Mondesire et al, 2004;Faried et al, 2006;Aissat et al, 2007). In vitro, paclitaxel treatment before mTOR inhibition produced greater enhancement of apoptosis than treatment after or simultaneously with the mTOR inhibitor, which may reflect a conflict between the slowing of the cell cycle through the G 1 -S transition by mTOR inhibition and the requirement that cells be in G 2 -M transition for paclitaxelinduced apoptosis (Mondesire et al, 2004;Aissat et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…However, in another study with cervical cancer cells, treatment with rapamycin preceding paclitaxel produced the more favourable result (Faried et al, 2006), suggesting that sequence dependency may be influenced by different mechanisms in other types of cancer. Inhibition of protein synthesis by mTOR inhibition may additionally contribute to apoptosis by preventing repair of paclitaxel-induced cell damage (Aissat et al, 2007). The extent to which sequence dependency translates in vivo is also not clear.…”

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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“…Everolimus (Afinitor Ò , Novartis Pharmaceuticals Corporation, East Hanover, NJ), an mTORC1 inhibitor, sensitizes cancer cell lines to platinum and taxane CT [63]. Despite much interest in the use of induction CT, well-designed studies have found no improvement in overall survival with induction CT followed by chemoradiation versus chemoradiation alone (DeCIDE study [64], PARADIGM study [65]).…”

Section: Mtor Inhibitionmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

2015

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Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines

Cited by 91 publications

References 25 publications

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

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

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

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

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