A new era of improving progression-free survival with dual blockade in postmenopausal HR+, HER2− advanced breast cancer

Jérusalem, Guy; Bachelot, Thomas; Barrios, Carlos H.; Neven, Patrick; Leo, Angelo Di; Janni, Wolfgang; Boer, Richard de

doi:10.1016/j.ctrv.2014.12.011

Cited by 24 publications

(24 citation statements)

References 54 publications

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“…AZD2014 induces a more complete growth inhibition and cell death in vitro compared with everolimus in a number of cell lines. ER þ cell lines are amongst the most sensitive to AZD2014, consistent with the PI3K-mTOR pathway being important in this setting (17,18). In vivo, AZD2014 causes significant tumor growth inhibition in a number of xenograft and patient derived models.…”

Section: Discussionmentioning

confidence: 76%

“…Although aromatase inhibitors have become standard of care in postmenopausal women and endocrine therapy is generally very effective, disease progression remains a major challenge in this setting. Recent advances in elucidating the molecular mechanisms of pathway "cross-talk" between the estrogen receptor (ER) and intracellular signaling pathways, including the PI3K-mTOR pathway (17), have provided the rationale for combining endocrine therapies with a targeted agent against a compensatory pathway (18). In the BOLERO-2 trial, the inhibitor everolimus, in combination with exemestane, improved progression-free survival of patients with advanced breast cancer previously treated with aromatase inhibitors, leading to its approval by the FDA (19).…”

Section: Introductionmentioning

confidence: 99%

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AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules

Guichard

Curwen

Bihani

et al. 2015

Molecular Cancer Therapeutics

106

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mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. mTOR is part of the multiprotein complexes mTORC1 and mTORC2, which have been shown to play critical yet functionally distinct roles in the regulation of cellular processes. Current clinical mTOR inhibitors only inhibit the mTORC1 complex and are derivatives of the macrolide rapamycin (rapalogs). Encouraging effects have been observed with rapalogs in estrogen receptor-positive (ER þ ) breast cancer patients in combination with endocrine therapy, such as aromatase inhibitors. AZD2014 is a small-molecule ATP competitive inhibitor of mTOR that inhibits both mTORC1 and mTORC2 complexes and has a greater inhibitory function against mTORC1 than the clinically approved rapalogs. Here, we demonstrate that AZD2014 has broad antiproliferative effects across multiple cell lines, including ER þ breast models with acquired resistance to hormonal therapy and cell lines with acquired resistance to rapalogs. In vivo, AZD2014 induces dose-dependent tumor growth inhibition in several xenograft and primary explant models. The antitumor activity of AZD2014 is associated with modulation of both mTORC1 and mTORC2 substrates, consistent with its mechanism of action. In combination with fulvestrant, AZD2014 induces tumor regressions when dosed continuously or using intermittent dosing schedules. The ability to dose AZD2014 intermittently, together with its ability to block signaling from both mTORC1 and mTORC2 complexes, makes this compound an ideal candidate for combining with endocrine therapies in the clinic. AZD2014 is currently in phase II clinical trials.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules

Guichard

Curwen

Bihani

et al. 2015

Molecular Cancer Therapeutics

106

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show abstract

“…The new knowledge about molecular mechanisms regulating tumor progression, suggested the existence of a strict relationship between ERs, intracellular signaling pathways, and other growth factors receptor, which justify the escape of a portion of patients from the inhibitory effects of ET [58] . To restore endocrine sensitivity of ER+ cancer cells, several other drugs have been studied, including cyclin-dependent kinase (CDK) 4/6 inhibitors (palbociclib), epigenetic modulators that inhibit histone deacetylase (HDAC), and other signal pathway inhibitors [59] .…”

Section: Endocrine Therapy and Molecular-target Therapymentioning

confidence: 99%

“…The combination anastrozole and fulvestrant in metastatic ER+ BC was superior to anastrozole alone [41] . All endocrine therapies, in particular AIs, synergize their effects with several molecular target drugs, such as everolimus and palbociclib [58,60] . It has also been shown that exemestane plus everolimus were more efficacious than everolimus alone and fulvestrant alone in women with advanced BC and progressive disease [52,63] .…”

Section: Metastatic Breast Cancermentioning

confidence: 99%

Current medical treatment of estrogen receptor-positive breast cancer

Lumachi

Santeufemia

Basso

2015

WJBC

168

126

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Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (1) ovarian function suppression (OFS), usually obtained using gonadotropinreleasing hormone agonists (GnRHa); (2) selective estrogen receptor modulators or down-regulators (SERMs or SERDs); and (3) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e. , tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ , especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e. , fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e. , anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

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“…Estrogen-positive metastatic breast cancer cannot be cured currently 1. One major metastatic site of breast cancer is bone.…”

Section: Introductionmentioning

confidence: 99%

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

Kast¹,

Skuli

Cos

et al. 2017

BCTT

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Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways – RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E – that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial.

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A new era of improving progression-free survival with dual blockade in postmenopausal HR+, HER2− advanced breast cancer

Cited by 24 publications

References 54 publications

AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules

AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules

Current medical treatment of estrogen receptor-positive breast cancer

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

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