Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells

Treeck, Oliver; Wackwitz, Birgit; Haus, Ulrike; Ortmann, O.

doi:10.1016/j.ygyno.2005.12.019

Cited by 91 publications

(70 citation statements)

References 19 publications

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“…Furthermore, the effect of the combination of letrozole with RAD001 in two models of breast carcinoma (MCF-7 and T47D cells) demonstrated that estrogen-induced proliferation is largely dependent on mTOR signaling and that RAD001 in combination with letrozole has more profound effects on aromatase-mediated estrogen-induced proliferation than either agent alone [5]. Similar findings on growth inhibition have been reported for MCF-7 cells treated with RAD001 and tamoxifen [25]. Recent clinical findings from a phase II study conducted in 270 postmenopausal women with ER positive breast cancer in the neoadjuvant setting, showed that RAD001 caused tumour shrinkage when given in combination with letrozole.…”

Section: Mammalian Tor and The Efficacy Of Anti-hormonal Agentssupporting

confidence: 71%

“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

Margariti

Fox

Bottini

et al. 2010

Breast Cancer Res Treat

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The mTOR pathway is pivotal not only in tumorigenesis but also in chemotherapy and hormonal drug sensitivity. It is clear that improvements in using new targeted therapies are required to improve breast cancer (BC) outcome. Nevertheless, to achieve this, new molecular biomarkers are required to define the potential sensitivity or resistance of cancer cells. By targeting the mTOR pathway, several critical central transduction pathways that sustain breast cancer are abrogated (HER-2/Neu and the estrogen receptor pathway). Thus the compounds that inhibit mTOR have a double mechanism of toxicity on BC cells when used in combination with a currently used drug: 1) overcoming primary drug resistance and 2) restoring sensitivity when resistance arises after longterm exposure. This review covers the utility of inhibitors of the mTOR pathway in BC and emphasizes the new paradigm of close symbiosis between oncology and molecular biology to better profiling and treating BC with a targeted approach. In particular, we focused on the new drug RAD001 (Everolimus) due to the great results from preclinical and clinical trials make it the most hopeful compound among mTOR inhibitors for the treatment of BC.

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Section: Mammalian Tor and The Efficacy Of Anti-hormonal Agentssupporting

confidence: 71%

“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

Margariti

Fox

Bottini

et al. 2010

Breast Cancer Res Treat

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“…Receptor subtype status of SKOV3 had been controversial in the literature. SKOV3 was reported to be ERa-negative and ERb-positive (Treeck et al 2006) and it had also been described as estrogenunresponsive because it expresses a dysfunctional ERa and very low levels of ERb (Jones et al 1994, Lau et al 1999. However, we demonstrated by western blotting that SKOV3 expressed both receptors, although the expression of ERa was higher than that of ERb in the ratio of 57:1 by quantitative real-time PCR, which is compatible with the findings of O'Donnell et al (2005) and we demonstrated that this cell line was responsive to estrogen.…”

Section: Discussionmentioning

confidence: 99%

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Chan

Leung

Chan

et al. 2014

Journal of Endocrinology

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Ovarian cancer cells express both estrogen receptor a (ERa) and ERb, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERa compared with ERb, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.

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“…Everolimus (RAD001, Novartis, Basel, Switzerland), a novel rapamycin derivative, is a potent mTOR inhibitor that does not share the problems of poor solubility and chemical stability of rapamycin [10]. Everolimus displays direct inhibitory effects on breast cancer cell growth and proliferation in preclinical models [11][12][13]. Clinical trials, including Phase-II trials in breast cancer, have tested the efficacy of everolimus treatment either as a monotherapy or in combination with letrozole.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer

Sabine

Sims

Macaskill

et al. 2010

Breast Cancer Res Treat

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There is growing evidence that uncontrolled activation of the PI3K/Akt/mTOR pathway contributes to the development and progression of breast cancer. Inhibition of this pathway has antitumour effects in preclinical studies and efficacy in combination with other agents in breast cancer patients. The aim of this study is to characterise the effects of pre-operative everolimus treatment in primary breast cancer patients and to identify potential molecular predictors of response. Twenty-seven patients with oestrogen receptor (ER)-positive breast cancer completed 11-14 days of neoadjuvant treatment with 5-mg everolimus. Core biopsies were taken before and after treatment and analysed using Illumina HumanRef-8 v2 Expression BeadChips. Changes in proliferation (Ki67) and phospho-AKT were measured on diagnostic core biopsies/resection samples embedded in paraffin by immunohistochemistry to determine response to treatment. Patients that responded to everolimus treatment with significant reductions in proliferation (fall in % Ki67 positive cells) also had significant decreases in the expression of genes involved in cell cycle (P = 8.70E-09) and p53 signalling (P = 0.01) pathways. Highly proliferating tumours that have a poor prognosis exhibited dramatic reductions in the expression of cell cycle genes following everolimus treatment. The genes that most clearly separated responding from nonresponding pre-treatment tumours were those involved with protein modification and dephosphorylation, including DYNLRB2, ERBB4, PTPN13, ULK2 and DUSP16. The majority of ER-positive breast tumours treated with everolimus showed a significant reduction in genes involved with proliferation, these may serve as markers of response and predict which patients will derive most benefit from mTOR inhibition.

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Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells

Cited by 91 publications

References 19 publications

“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer

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