Preclinical studies of the combination of RAD001 with tamoxifen or letrozole in breast cancer

Farmer, Ian; Evans, M. D.; Lane, Heidi A.; Lykkesfeldt, A. E.; Dowsett, Mitch; Martín, Luis Miguel Navarro

doi:10.1016/s1359-6349(06)80344-7

Cited by 3 publications

(3 citation statements)

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“…Studies are ongoing evaluating the value of adding everolimus (RAD001) to letrozole as preoperative therapy of primary breast cancer [NCT 0010116]. In preclinical studies, RAD001 treatment of endocrine-sensitive and endocrine-resistant breast cancer cell lines resulted in a dose-dependant decrease in proliferation and estrogen receptor alpha mediated transcription [76].…”

Section: Rapamycin Analoguesmentioning

confidence: 99%

Overcoming endocrine resistance in breast cancer—are signal transduction inhibitors the answer?

Bedard

Freedman

Howell

et al. 2007

Breast Cancer Res Treat

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Endocrine therapy is probably the most important systemic therapy for hormone receptor positive breast cancer. Hormonal manipulation was the first targeted treatment employed in breast cancer therapy even before the role of the estrogen (ER) and progesterone receptors (PR) had been elucidated. Unfortunately, a substantial proportion of patients, despite being ER and/or PR positive, are either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Signaling through complex growth factor receptor pathways, which activate the ER are emerging as important causes of endocrine resistance. Targeted therapies, such as signal transduction inhibitors (STIs), are being explored as agents to be able to potentially overcome this crosstalk and thus, resistance to hormone treatment. This article reviews the biology of the ER, the proposed mechanisms of endocrine resistance, and ongoing clinical trials with STIs in combination with hormonal manipulation as a means to overcome endocrine resistance.

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Section: Rapamycin Analoguesmentioning

confidence: 99%

Overcoming endocrine resistance in breast cancer—are signal transduction inhibitors the answer?

Bedard

Freedman

Howell

et al. 2007

Breast Cancer Res Treat

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“…Another interesting therapeutic target is mTOR, a central regulator of G1 cell cycle protein synthesis, that precedes commitment to normal cellular replication [ 46 ]. Treatment of MCF-7 Arom-1 cells with letrozole and the mTOR inhibitor RAD001 resulted in a further 50% reduction in proliferation compared with letrozole alone [ 47 ]. Another set of experiments, developed to test the hypothesis that Akt kinase confers resistance to endocrine therapy through suppression of ASK1/JNK pathway, showed that combining RAD001 with letrozole restored activation of the ASK/JNK pathway and increased the sensitivity of MCF-7 cells with constitutively active Akt to endocrine therapy [ 48 ].…”

Section: Combination Therapymentioning

confidence: 99%

Femara® and the future: tailoring treatment and combination therapies with Femara

Ellis¹,

Ma²

2007

Breast Cancer Res Treat

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Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the reemergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance. Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs.

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“…Le système m-TOR qui est un des effecteurs de la voie PI3K/Akt joue un rôle important dans la régu-lation de la prolifération cellulaire (phase G1-S du cycle cellulaire). Des données précliniques ont démontré une synergie d'action entre hormonothérapie et un inhibiteur m-TOR[8]. L'everolimus (RAD001) est un inhibiteur m-TOR actif par voie orale qui a montré des résultats positifs en combinaison avec le letrozole en préopéra-toire dans le traitement du cancer du sein RO+.Une étude randomisée de phase II a évalué le bénéfice et la tolérance de l'association letrozole (2,5 mg) et everolimus (RAD001) [10 mg/j] versus letrozole plus placebo pour un traitement de quatre mois en pré-opératoire chez 270 patientes postménopausées porteuses de cancer du sein RO+(Fig.…”

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Combination of targeted therapy-endocrine therapy in breast cancer

et al. 2010

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Approximately 70-80% of breast cancers expressed estrogen receptors (ER). Endocrine therapy is the main pillar of the medical management of women with ER+ breast cancer. Since its use, endocrine treatment has radically changed the fate of breast cancer ER + with marked improvement of progression-free survival and overall survival. However, the benefits of the endocrine therapy are limited by the development of resistance. Experimental studies concluded that resistance to the endocrine therapy occurs at least in part via activation of several intracellular signal transduction pathways of cell proliferation. These observations have encouraged a number of phase II/III clinical trials evaluating different approaches of using the signal transduction inhibitors (STI) in combination with endocrine agents. These trials evaluated the feasibility and the capacity of these combinations to delay or to prevent endocrine resistance and are reviewed hereunder.

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Preclinical studies of the combination of RAD001 with tamoxifen or letrozole in breast cancer

Cited by 3 publications

References 0 publications

Overcoming endocrine resistance in breast cancer—are signal transduction inhibitors the answer?

Overcoming endocrine resistance in breast cancer—are signal transduction inhibitors the answer?

Femara® and the future: tailoring treatment and combination therapies with Femara

Combination of targeted therapy-endocrine therapy in breast cancer

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