Publications of Pierre FOIDART
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See detailBRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
Coussy, F.; El-Botty, R.; Château-Joubert, S. et al

in Science Translational Medicine (2020), 12(532),

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast ... [more ▼]

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors. Copyright © 2020 The Authors, some rights reserved. [less ▲]

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See detailMT4-MMP: The GPI-Anchored Membrane-Type Matrix Metalloprotease with Multiple Functions in Diseases
Yip, Cassandre ULiege; FOIDART, Pierre ULiege; Noël, Agnès ULiege et al

in International Journal of Molecular Sciences (2019), 20 (2)

MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes ... [more ▼]

MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes, including embryogenesis, organogenesis, tissue regeneration, angiogenesis, wound healing, and inflammation. MT4-MMP (MMP17) presents unique characteristics compared to other members of the family in terms of sequence homology, substrate specificity, and internalization mode, suggesting distinct physiological and pathological functions. While the physiological functions of MT4-MMP are poorly understood, it has been involved in different pathological processes such as arthritis, cardiovascular disease, and cancer progression. The mt4-mmp transcript has been detected in a large diversity of cancers. The contribution of MT4-MMP to tumor development has been further investigated in gastric cancer, colon cancer, head and neck cancer, and more deeply in breast cancer. Given its contribution to different pathologies, particularly cancers, MT4-MMP represents an interesting therapeutic target. In this review, we examine its biological and structural properties, and we propose an overview of its physiological and pathological functions. [less ▲]

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See detailDiagnostic différentiel de l’anémie dans la cirrhose éthylique
Delmotte, Valentine ULiege; Foidart, Pierre ULiege; DE VOEGHT, Adrien ULiege et al

in Revue Médicale de Liège (2019), 74(10), 527-534

We report here the case of a 62-year-old patient with Child-Pugh stage C ethylic cirrhosis associated with severe macrocytic anaemia, refractory to iterative transfusions and withdrawal. After a ... [more ▼]

We report here the case of a 62-year-old patient with Child-Pugh stage C ethylic cirrhosis associated with severe macrocytic anaemia, refractory to iterative transfusions and withdrawal. After a haemorrhagic, deficiency-related, or sideroblastic etiology was ruled out, haemolytic anaemia was suspected. A blood smear allowed diagnosis of haemolytic anaemia with acanthocytes. This offers the opportunity to discuss anaemia in patients with alcoholic cirrhosis, a frequent complication spanning a broad severity range and having the potential to be life-threatening. Its origin can be multifactorial : acute haemorrhage, dilution, haemolysis (here due to acanthocytosis), marrow insufficiency caused by direct alcohol toxicity, malnutrition, iron deficiency, vitamin B9 or B12 deficiency, chronic inflammation, splenic sequestration induced by portal hypertension...Nous rapportons le cas d’une patiente de 62 ans atteinte d’une cirrhose éthylique de stade Child-Pugh C associée à une anémie macrocytaire sévère, réfractaire aux transfusions itératives et au sevrage. Après avoir exclu les étiologies hémorragiques, carentielles et sidéroblastiques, une anémie hémolytique (AH) est suspectée. La réalisation d’un frottis sanguin a permis le diagnostic d’une anémie hémolytique à acanthocytes. L’opportunité nous est donnée de discuter de l’anémie chez le patient cirrhotique alcoolique, complication fréquente recouvrant un large spectre de gravité et pouvant menacer la survie. Elle peut être multifactorielle : hémorragie aiguë, dilution, hémolyse (dans le cas particulier, liée à une acanthocytose), insuffisance médullaire par toxicité directe de l’alcool, malnutrition, carence martiale, déficit en vitamine B9 ou B12, inflammation chronique, séquestration splénique induite par l’hypertension portale…. [less ▲]

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See detailExpression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy.
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

in Clinical Cancer Research (2019)

Abstract Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived ... [more ▼]

Abstract Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB).Experimental Design: IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in vitro in 2D and 3D proliferation assays and in vivo using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib + palbociclib) treatments.Results: EGFR and MT4-MMP were coexpressed in >70% of TNBC samples and PDX-TNBC, among which approximately 60% maintained RB expression. Notably, approximately 50% of all TNBC and PDX-TNBC expressed the three biomarkers. Single erlotinib and palbociclib treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared with control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR, and RB, but not PDX-TNBC with RB loss, were sensitive to erlotinib and palbociclib with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to erlotinib alone.Conclusions: We defined a new association of three biomarkers (MT4-MMP/EGFR/RB) expressed together in 50% of TNBC and demonstrated its usefulness to predict the TNBC response to anti-EGFR and anti-CDK4/6 drugs used in single or combined therapy. [less ▲]

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See detailMT4-MMP, EGFR and RB expressions are predictive biomarkers of response to Erlotinib-Palbociclib combination in TNBC
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

Conference (2018, February 24)

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See detailExpression of MT4-MMP, EGFR and Rb in triple negative breast cancers strongly sensitizes tumors to Erlotinib and Palbociclib combination therapy
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

Scientific conference (2018, January 27)

Triple negative breast cancer (TNBC) comprises heterogeneous tumors displaying an aggressive pattern of progression and metastasis. The standard systemic treatment relies entirely on chemotherapy. While ... [more ▼]

Triple negative breast cancer (TNBC) comprises heterogeneous tumors displaying an aggressive pattern of progression and metastasis. The standard systemic treatment relies entirely on chemotherapy. While epidermal growth factor receptor (EGFR) is frequently over-expressed in TNBC, targeted therapies against EGFR did not show clinical benefit. Recently, we demonstrated that EGFR interacts with MT4-MMP, the membrane-type 4 matrix metalloproteinase in TNBC. Also, based on an immunohistochemistry (IHC) analysis we reported that EGFR and MT4-MMP are co-expressed in 79 % of human TNBC samples. Here, we identified MT4-MMP/EGFR axis as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein (Rb) inactivation. Finally, we investigated the significance of targeting EGFR and CDK4 in TNBC expressing MT4-MMP and EGFR. [less ▲]

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See detailCapecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers.
Marangoni, Elisabetta; Laurent, Cecile; Coussy, Florence et al

in Clinical Cancer Research (2018)

PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to ... [more ▼]

PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. EXPERIMENTAL DESIGN: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. RESULTS: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naive derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. CONCLUSIONS: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response. [less ▲]

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See detailMT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib.
Yip, Cassandre ULiege; Foidart, Pierre ULiege; Somja, Joan ULiege et al

in British Journal of Cancer (2017)

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a ... [more ▼]

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. METHODS: We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays. RESULTS: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. CONCLUSIONS: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.British Journal of Cancer advance online publication 14 February 2017; doi:10.1038/bjc.2017.23 www.bjcancer.com. [less ▲]

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See detailMT4-MMP, a potential prognostic factor in triple negative breast cancer
Yip, Cassandre ULiege; FOIDART, Pierre ULiege; SOMJA, Joan ULiege et al

Scientific conference (2015, December 03)

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See detailMT4-MMP, a potential therapeutic target in triple negative breast cancer
Yip, Cassandre ULiege; FOIDART, Pierre ULiege; SOMJA, Joan ULiege et al

Poster (2015, September)

MT4-MMP and EGFR axis may have a significant role in patient outcome and response to EGFR targeted therapy. This axis is clinically relevant in TNBC, the most aggressive breast cancer subtype. TNBC are ... [more ▼]

MT4-MMP and EGFR axis may have a significant role in patient outcome and response to EGFR targeted therapy. This axis is clinically relevant in TNBC, the most aggressive breast cancer subtype. TNBC are known to express high level of EGFR and treatment options are limited due to the non response of to the EGFR targeted therapy. Expression levels of MT4-MMP and EGFR in TNBC may be used as prognosis factor for the selection of patient who may respond or not to EGFR targeted therapy. Also, our data shed light and the potential therapeutic option of targeting both MT4-MMP and EGFR in TNBC. [less ▲]

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