A phase II study of oral mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), in patients with recurrent endometrial carcinoma (EC)

Slomovitz, Brian M.; Lu, Karen H.; Johnston, Taren; Munsell, Melissa; Ramondetta, Lois M.; Broaddus, R.; Coleman, R.L.; Walker, Colin; Gershenson, D. M.; Burke, Thomas W.; Wolf, J.

doi:10.1200/jco.2008.26.15_suppl.5502

Cited by 34 publications

(23 citation statements)

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“…Moreover, the combination of PTEN/p-AKT expression has been reported to be a prognostic indicator for patients with advanced endometrial cancer, as patients with PTEN-positive and p-AKT-negative expressing tumors exhibited a higher overall survival rate (38). It has been reported that PTEN loss may predict clinical benefit response in advanced endometrial cancer patients in a trial using everolimus (RAD001), another rapamycin analogue (39). Conversely, however, PTEN status appeared not to be predictive of response in a separate trial of this disease with the mTOR inhibitor temsirolimus (CCI-779; ref.…”

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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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: 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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“…The rapalogs have been investigated as monotherapy in a host of other phase II studies in diverse tumor types, including neuroendocrine tumors, breast cancer, endometrial cancer and sarcomas [43]. Encouraging single agent clinical efficacy was observed with the use of everolimus in pretreated patients with recurrent endometrial cancer, where loss of PTEN expression was predictive of clinical benefit [44].…”

Section: Mtor Inhibitors -The Rapalogsmentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

2010

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AbstrAct:It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.

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“…In endometrial cancers, which have early PTEN loss, tumor regression has rarely been observed, despite stabilization of disease by rapalogs in 26%-44% of those treated in two small phase II studies (78,79). Moreover, while breast cancers show frequent PI3K activation (7), via HER2 amplification, overexpression of IGF-1R or EGFR, PIK3CA mutation, or PTEN loss, the activity of temsirolimus (ORR, 7%-10%) (88) and everolimus (ORR, 12%) (89) as single-agent therapies was disappointing in individuals with metastatic breast cancer.…”

Section: Rapamycin and Rapalogs As Anticancer Therapiesmentioning

confidence: 99%

“…Temsirolimus yielded a 22% overall response rate (ORR, which represents complete or partial responses divided by the number of patients treated) in a phase III trial for refractory mantle cell lymphoma, in contrast to only 2% for investigator's choice of therapy (73). Similarly, rapalogs showed single-agent activity against other types of lymphomas (74)(75)(76) and are being evaluated in phase II trials for sarcomas, endometrial cancers, and other advanced solid tumors (77)(78)(79). For example, a recent phase I study of everolimus showed promise in patients with advanced colorectal cancer (80).…”

Section: Rapamycin and Rapalogs As Anticancer Therapiesmentioning

confidence: 99%

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Wander¹,

Hennessy²,

Slingerland³

2011

J. Clin. Invest.

372

363

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A phase II study of oral mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), in patients with recurrent endometrial carcinoma (EC)

Cited by 34 publications

References 0 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

Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

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