Therapy of breast cancer brain metastases: challenges, emerging treatments and perspectives

Kotecki, Nuria; Lefranc, Florence; Devriendt, Daniel; Awada, Ahmad

doi:10.1177/1758835918780312

Cited by 43 publications

(44 citation statements)

References 80 publications

(108 reference statements)

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“…Moreover, the BBB and the crosstalk between malignant and brain cells favor brain metastasis (Wilhelm et al , ). Altogether, this renders the brain a sanctuary against antitumor strategies, hindering the treatment of brain metastases with the available current therapies (Kotecki et al , ).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of circulating miR 802‐5p and miR 194‐5p and upregulation of brain MEF2C along breast cancer brain metastasization

et al. 2020

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Breast cancer brain metastases (BCBMs) have been underinvestigated despite their high incidence and poor outcome. MicroRNAs (miRNAs), and particularly circulating miRNAs, regulate multiple cellular functions, and their deregulation has been reported in different types of cancer and metastasis. However, their signature in plasma along brain metastasis development and their relevant targets remain undetermined. Here, we used a mouse model of BCBM and next‐generation sequencing (NGS) to establish the alterations in circulating miRNAs during brain metastasis formation and development. We further performed bioinformatics analysis to identify their targets with relevance in the metastatic process. We additionally analyzed human resected brain metastasis samples of breast cancer patients for target expression validation. Breast cancer cells were injected in the carotid artery of mice to preferentially induce metastasis in the brain, and samples were collected at different timepoints (5 h, 3, 7, and 10 days) to follow metastasis development in the brain and in peripheral organs. Metastases were detected from 7 days onwards, mainly in the brain. NGS revealed a deregulation of circulating miRNA profile during BCBM progression, rising from 18% at 3 days to 30% at 10 days following malignant cells’ injection. Work was focused on those altered prior to metastasis detection, among which were miR‐802‐5p and miR‐194‐5p, whose downregulation was validated by qPCR. Using targetscan and diana tools, the transcription factor myocyte enhancer factor 2C (MEF2C) was identified as a target for both miRNAs, and its expression was increasingly observed in malignant cells along brain metastasis development. Its upregulation was also observed in peritumoral astrocytes pointing to a role of MEF2C in the crosstalk between tumor cells and astrocytes. MEF2C expression was also observed in human BCBM, validating the observation in mouse. Collectively, downregulation of circulating miR‐802‐5p and miR‐194‐5p appears as a precocious event in BCBM and MEF2C emerges as a new player in brain metastasis development.

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Section: Introductionmentioning

confidence: 99%

Downregulation of circulating miR 802‐5p and miR 194‐5p and upregulation of brain MEF2C along breast cancer brain metastasization

et al. 2020

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“…With better control of systemic disease, many women who have stable primary disease, or respond to initial treatment, ultimately develop BCBM. Thus, while survival of primary breast cancer is improving, the incidence of BCBM is increasing 2 .…”

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confidence: 99%

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

et al. 2020

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Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; however, mechanisms governing adaptation to the brain microenvironment remain poorly defined. We combine time-course RNA-sequencing of BCBM development with a Drosophila melanogaster genetic screen, and identify Rab11b as a functional mediator of metastatic adaptation. Proteomic analysis reveals that Rab11b controls the cell surface proteome, recycling proteins required for successful interaction with the microenvironment, including integrin β1. Rab11b-mediated control of integrin β1 surface expression allows efficient engagement with the brain ECM, activating mechanotransduction signaling to promote survival. Lipophilic statins prevent membrane association and activity of Rab11b, and we provide proof-of principle that these drugs prevent breast cancer adaptation to the brain microenvironment. Our results identify Rab11b-mediated recycling of integrin β1 as regulating BCBM, and suggest that the recycleome, recycling-based control of the cell surface proteome, is a previously unknown driver of metastatic adaptation and outgrowth.

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“…In contrast, there are limited targeted therapies available with modest therapeutic responses to target distant metastasis in ERBB2 + BC patients [ 3 , 44 , 45 ]. The optimization of targeted therapies against metastatic ERBB2 + BC is challenging for several reasons, including molecular and metabolic adaptations in metastasizing cells, refractive organ-specific microenvironments, and lack of preclinical models to evaluate therapeutic targets [ 9 , 46 , 47 , 48 ]. In this study, we reported an orthotopic model of spontaneous ERBB2 + BC BrM that can be used to evaluate therapeutic approaches targeting both the primary tumor and distant metastases together, suggesting its high clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

“…The poor therapeutic response towards targeted therapies in metastatic ERBB2 + BC is attributed in part to clonal evolution in metastatic cells, their adaptation to the organ-specific microenvironment, and differential drug delivery to the metastatic niche [ 4 , 5 , 6 ]. This is exemplified by the presence of the blood–brain barrier (BBB) in the case of BrM, which has one of the poorest outcomes among all metastatic BCs [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

Gautam

Kanchan

Siddiqui

et al. 2020

Cancers

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Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC.

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Therapy of breast cancer brain metastases: challenges, emerging treatments and perspectives

Cited by 43 publications

References 80 publications

Downregulation of circulating miR 802‐5p and miR 194‐5p and upregulation of brain MEF2C along breast cancer brain metastasization

Downregulation of circulating miR 802‐5p and miR 194‐5p and upregulation of brain MEF2C along breast cancer brain metastasization

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

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