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1. In vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in human chordoma xenografts

Author

Thibault Passeri, Ahmed Dahmani, Julien Masliah-Planchon, Rania El Botty, Laura Courtois, Sophie Vacher, Elisabetta Marangoni, Fariba Nemati, Sergio Roman-Roman, Homa Adle-Biassette, Hamid Mammar, Sébastien Froelich, Ivan Bièche, and Didier Decaudin

Subjects
CDKN2A/2B deletion, chordoma patient’s derived xenograft, CDK4/6 inhibitor, palbocicib, PLK1 inhibitor, volasertib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

BackgroundManagement of advanced chordomas remains delicate considering their insensitivity to chemotherapy. Homozygous deletion of the regulatory gene CDKN2A has been described as the most frequent genetic alteration in chordomas and may be considered as a potential theranostic marker. Here, we evaluated the tumor efficacy of the CDK4/6 inhibitor palbociclib, as well as the PLK1 inhibitor volasertib, in three chordoma patient-derived xenograft (PDX) models to validate and identify novel therapeutic approaches.MethodsFrom our chordoma xenograft panel, we selected three models, two of them harboring a homozygous deletion of CDKN2A/2B genes, and the last one a PBRM1 pathogenic variant (as control). For each model, we tested the palbociclib and volasertib drugs with pharmacodynamic studies together with RT-PCR and RNAseq analyses.ResultsFor palbociclib, we observed a significant tumor response for one of two models harboring the deletion of CDKN2A/2B (p = 0.02), and no significant tumor response in the PBRM1-mutated PDX; for volasertib, we did not observe any response in the three tested models. RT-PCR and RNAseq analyses showed a correlation between cell cycle markers and responses to palbociclib; finally, RNAseq analyses showed a natural enrichment of the oxidative phosphorylation genes (OxPhos) in the palbociclib-resistant PDX (p = 0.02).ConclusionCDK4/6 inhibition appears as a promising strategy to manage advanced chordomas harboring a loss of CDKN2A/2B. However, further preclinical studies are strongly requested to confirm it and to understand acquired or de novo resistance to palbociclib, in the peculiar view of a targeting of the oxidative phosphorylation genes.

Published
2022
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2. Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant

Author

Julien Jacquemetton, Loay Kassem, Coralie Poulard, Ahmed Dahmani, Ludmilla De Plater, Elodie Montaudon, Laura Sourd, Ludivine Morisset, Rania El Botty, Sophie Chateau-Joubert, Sophie Vacher, Ivan Bièche, Isabelle Treilleux, Olivier Trédan, Elisabetta Marangoni, and Muriel Le Romancer

Subjects
Breast cancer, Estrogen signaling, Resistance, PI3K, PDX, Biomarker, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ERα-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylERα/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. Methods The interaction of ERα/Src and ERα/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ERα+ and 3 ERα− PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ERα/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ERα/Src and ERα/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ERα+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ERα/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ERα signaling, since genomic degradation of ERα was unaltered in these tumors, whereas the treatment did not diminish the level of ERα/PI3K interaction. Interestingly, in 2 ERα− models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ERα/PI3K interaction. Conclusions Our results demonstrate that ERα/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ERα+ tumors was associated with a lack of impairment of ERα/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ERα/PI3K in ERα− tumors could constitute a promising therapeutic option.

Published
2021
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3. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Author

Elodie Montaudon, Joanna Nikitorowicz-Buniak, Laura Sourd, Ludivine Morisset, Rania El Botty, Léa Huguet, Ahmed Dahmani, Pierre Painsec, Fariba Nemati, Sophie Vacher, Walid Chemlali, Julien Masliah-Planchon, Sophie Château-Joubert, Camilla Rega, Mariana Ferreira Leal, Nikiana Simigdala, Sunil Pancholi, Ricardo Ribas, André Nicolas, Didier Meseure, Anne Vincent-Salomon, Cécile Reyes, Audrey Rapinat, David Gentien, Thibaut Larcher, Mylène Bohec, Sylvain Baulande, Virginie Bernard, Didier Decaudin, Florence Coussy, Muriel Le Romancer, Guillaume Dutertre, Zakia Tariq, Paul Cottu, Keltouma Driouch, Ivan Bièche, Lesley-Ann Martin, and Elisabetta Marangoni

Subjects
Science
Abstract

Identifying novel therapies for the treatment of CDK4/6 inhibitor-resistant patients is of great importance. Here, the authors demonstrate that PLK1 inhibition is a potential therapeutic target in CCND1-driven and in RB-positive Palbociclib-resistant breast cancers.

Published
2020
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4. Dramatic In Vivo Efficacy of the EZH2-Inhibitor Tazemetostat in PBRM1-Mutated Human Chordoma Xenograft

Author

Thibault Passeri, Ahmed Dahmani, Julien Masliah-Planchon, Adnan Naguez, Marine Michou, Rania El Botty, Sophie Vacher, Rachida Bouarich, André Nicolas, Marc Polivka, Coralie Franck, Anne Schnitzler, Fariba Némati, Sergio Roman-Roman, Franck Bourdeaut, Homa Adle-Biassette, Hamid Mammar, Sébastien Froelich, Ivan Bièche, and Didier Decaudin

Subjects
Cancer Research, Oncology, chordoma, patient-derived xenografts, next-generation sequencing, EZH2 inhibitor, targeted therapy
Abstract

Chordomas are rare neoplasms characterized by a high recurrence rate and a poor long-term prognosis. Considering their chemo-/radio-resistance, alternative treatment strategies are strongly required, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complexes are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this pathology. Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (p = 0.007). All PDXs maintained the same histopathological features as patients’ tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a PBRM1 variant, an overall survival of 100% was observed. Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a PBRM1 variant supports further evaluation for EZH2-inhibitors in this subgroup of chordomas.

Published
2022
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5. HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast

Author

Cécile Reyes, David Gentien, Francesco Ricci, André Nicolas, Sophie Vacher, Elisabetta Marangoni, Florence Coussy, Fabien Reyal, Sophie Château-Joubert, Rania El-Botty, Caterina Marchiò, Anne Vincent-Salomon, Ahmed Dahmani, Elodie Montaudon, Ivan Bièche, and Marick Laé

Subjects
Cancer Research, medicine.medical_specialty, Pyridones, medicine.medical_treatment, Antineoplastic Agents, Breast Neoplasms, Pyrimidinones, Proto-Oncogene Proteins p21(ras), Breast cancer, Internal medicine, Oximes, medicine, Humans, Point Mutation, Diseases of the blood and blood-forming organs, HRAS, Breast, Molecular Biology, Letter to the Editor, Protein Kinase Inhibitors, RC254-282, PDX, Aged, Trametinib, Aged, 80 and over, Chemotherapy, MEK inhibitor, Hematology, Adenomyoepithelioma, business.industry, Imidazoles, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Dabrafenib, Middle Aged, medicine.disease, Oncology, Drug Resistance, Neoplasm, Cancer research, Female, RC633-647.5, business, medicine.drug
Abstract

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours’ samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.

Published
2021

6. Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant

Author

Muriel Le Romancer, Ahmed Dahmani, Ludivine Morisset, Coralie Poulard, Ivan Bièche, Loay Kassem, Isabelle Treilleux, Julien Jacquemetton, Sophie Vacher, Laura Sourd, Rania El Botty, Olivier Tredan, Ludmilla de Plater, Elodie Montaudon, Elisabetta Marangoni, Sophie Chateau-Joubert, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cairo University - Faculty of Medicine, Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Ecole Nationale Vétérinaire d'Alfort, École nationale vétérinaire - Alfort (ENVA), Centre Léon Bérard [Lyon], and Manship, Brigitte

Subjects
medicine.drug_class, Resistance, Proto-Oncogene Proteins pp60(c-src), Estrogen receptor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Proximity ligation assay, Biology, PI3K, 03 medical and health sciences, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Surgical oncology, Antineoplastic Combined Chemotherapy Protocols, medicine, Biomarkers, Tumor, PTEN, Animals, Humans, Fulvestrant, RC254-282, PI3K/AKT/mTOR pathway, 030304 developmental biology, PDX, Phosphoinositide-3 Kinase Inhibitors, 0303 health sciences, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Biomarker, Genomics, Middle Aged, Prognosis, Xenograft Model Antitumor Assays, Thiazoles, Receptors, Estrogen, Estrogen, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, Tamoxifen, Estrogen signaling, medicine.drug, Research Article, Signal Transduction
Abstract

Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ERα-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylERα/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. Methods The interaction of ERα/Src and ERα/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ERα+ and 3 ERα− PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ERα/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ERα/Src and ERα/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ERα+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ERα/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ERα signaling, since genomic degradation of ERα was unaltered in these tumors, whereas the treatment did not diminish the level of ERα/PI3K interaction. Interestingly, in 2 ERα− models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ERα/PI3K interaction. Conclusions Our results demonstrate that ERα/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ERα+ tumors was associated with a lack of impairment of ERα/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ERα/PI3K in ERα− tumors could constitute a promising therapeutic option.

Published
2021
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7. In vitro bone metastasis dwelling in a 3D bioengineered niche

Author

Frédéric Deschaseaux, Stéphanie Descroix, Anne Vincent-Salomon, Elodie Montaudon, Rania El Botty, Weijing Han, Nicolas Espagnolle, Laurent Malaquin, Luc Sensebé, Sergio Roman-Roman, Jacques Camonis, Pascal Silberzan, Franck Assayag, Paul Cottu, Maria Carla Parrini, Elisabetta Marangoni, Gérard Zalcman, Guillaume Dutertre, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Équipe Ingénierie pour les sciences du vivant (LAAS-ELIA), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), European Project: 760927,H2020-HoliFAB project, Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse Capitole (UT Capitole), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Silberzan, Pascal, and HoliFAB - H2020-HoliFAB project - 760927 - INCOMING

Subjects
3D-printing, Patient-derived-xenograft, Biophysics, Bone Neoplasms, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioengineering, 02 engineering and technology, Bone and Bones, Metastasis, Biomaterials, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomimetics, In vivo, Cell Line, Tumor, Tumor Microenvironment, medicine, Animals, Humans, Neoplasm Metastasis, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, 030304 developmental biology, 0303 health sciences, Osteoblasts, business.industry, Bone metastasis, Cancer, 021001 nanoscience & nanotechnology, medicine.disease, Metastatic breast cancer, In vitro, 3. Good health, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, Mechanics of Materials, Cancer cell, Ceramics and Composites, Cancer research, 0210 nano-technology, business, Model
Abstract

International audience; Bone is the most frequent metastasis site for breast cancer. As well as dramatically increasing disease burden, bone metastases are also an indicator of poor prognosis. One of the main challenges in investigating bone metastasis in breast cancer is engineering in vitro models that replicate the features of in vivo bone environments. Such in vitro models ideally enable the biology of the metastatic cells to mimic their in vivo behavior as closely as possible. Here, taking benefit of cutting-edge technologies both in microfabrication and cancer cell biology, we have developed an in vitro breast cancer bone-metastasis model. To do so we first 3D printed a bone scaffold that reproduces the trabecular architecture and that can be conditioned with osteoblast-like cells, a collagen matrix, and mineralized calcium. We thus demonstrated that this device offers an adequate soil to seed primary breast cancer bone metastatic cells. In particular, patient-derived xenografts being considered as a better approach than cell lines to achieve clinically relevant results, we demonstrate the ability of this biomimetic bone niche model to host patient-derived xenografted metastatic breast cancer cells. These patient-derived xenograft cells show a long-term survival in the bone model and maintain their cycling propensity, and exhibit the same modulated drug response as in vivo. This experimental system enables access to the idiosyncratic features of the bone microenvironment and cancer bone metastasis, which has implications for drug testing.

Published
2021
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8. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Author

Zakia Tariq, Sunil Pancholi, Nikiana Simigdala, Thibaut Larcher, Virginie Bernard, Mariana Ferreira Leal, Sophie Château-Joubert, Camilla Rega, Muriel Le Romancer, Fariba Nemati, Didier Decaudin, Ludivine Morisset, Anne Vincent-Salomon, Rania El Botty, Elisabetta Marangoni, Ahmed Dahmani, Cécile Reyes, Walid Chemlali, Audrey Rapinat, Ricardo Ribas, Guillaume Dutertre, Didier Meseure, Lesley-Ann Martin, Paul Cottu, Elodie Montaudon, Julien Masliah-Planchon, Sophie Vacher, Keltouma Driouch, Joanna Nikitorowicz-Buniak, Laura Sourd, Léa Huguet, Florence Coussy, Mylène Bohec, André Nicolas, Sylvain Baulande, Ivan Bièche, Pierre Painsec, David Gentien, Translational Research Department, Institut Curie, PSL Research University, Paris 75248, France, The institute of cancer research [London], Service de génétique, Institut Curie Paris, École nationale vétérinaire d'Alfort (ENVA), Department of pathology, Institut Curie, Institut Curie [Paris], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Expertise en Anatomie Pathologique (APEX), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Department of Medical Oncology, Institut Curie, Paris 75248, France, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie/ Departement de chirurgie/ 26 rue d'Ulm/ 75005 Paris, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and BABARIT, Candice

Subjects
0301 basic medicine, Pyridines, General Physics and Astronomy, Cell Cycle Proteins, 02 engineering and technology, Piperazines, Transcriptome, Mice, Breast cancer, Cyclin D1, lcsh:Science, Exome sequencing, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Pteridines, 021001 nanoscience & nanotechnology, Immunohistochemistry, 3. Good health, G2 Phase Cell Cycle Checkpoints, 0210 nano-technology, medicine.drug, DNA Copy Number Variations, Science, Immunoblotting, Anastrozole, Mice, Nude, Breast Neoplasms, Palbociclib, Protein Serine-Threonine Kinases, PLK1, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Targeted therapies, Cell Line, Tumor, Proto-Oncogene Proteins, Exome Sequencing, medicine, Animals, Humans, Immunoprecipitation, Cancer models, neoplasms, Cell growth, business.industry, General Chemistry, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, lcsh:Q, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment., Identifying novel therapies for the treatment of CDK4/6 inhibitor-resistant patients is of great importance. Here, the authors demonstrate that PLK1 inhibition is a potential therapeutic target in CCND1-driven and in RB-positive Palbociclib-resistant breast cancers.

Published
2020
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9. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

Author

Petra ter Brugge, Laetitia Fuhrmann, Fabien Reyal, Rania El-Botty, Thibaut Larcher, Laura Sourd, Sophie Château-Joubert, Agnès Noël, Jean-Luc Servely, Léa Huguet, Ivan Bièche, Pierre Foidart, Jos Jonkers, Philippe La Rosa, Pierre Painsec, Sophie Leboucher, Ludivine Morisset, Fariba Nemati, Georges Lucotte, Elodie Montaudon, Didier Decaudin, Christopher R. Mueller, Florence Coussy, Ahmed Dahmani, Marc-Henri Stern, Marie-France Poupon, Nor Eddine Sounni, Sophie Vacher, Adrien Briaux, Yves Pommier, Anne Vincent Salomon, Elisabetta Marangoni, Cécile Reyes, Tatiana Popova, Translational Research Department,Medical Oncology Department, Genetics Department, Institut Curie, Translational Research Department, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), PSL Research University, UMR3306, Département Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genetics Department, University of Santiago de Compostela, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), U830, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), Université de Liège, Translational Research Department, Medical Oncology Department, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Surgery Department, CRLCC Paul Strauss, U932, Immunity and Cancer, Queen's cancer reserach institute, Queen's University, Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, ProdInra, Archive Ouverte, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade de Santiago de Compostela [Spain] (USC ), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), PSL Research University, U900, and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes

Subjects
Anthracycline, DNA repair, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Triple Negative Breast Neoplasms, Topoisomerase-I Inhibitor, Irinotecan, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, CHEK1, skin and connective tissue diseases, 030304 developmental biology, 0303 health sciences, biology, Retinoblastoma, business.industry, Topoisomerase, Nuclear Proteins, General Medicine, medicine.disease, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Retinoblastoma Binding Proteins, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Topoisomerase I Inhibitors, business, Schlafen family member 11, medicine.drug
Abstract

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.

Published
2020
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10. Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts

Author

Leanne De Koning, Thibaut Larcher, Bérengère Ouine, Ivan Bièche, Rania El Botty, Anne Vincent Salomon, Ahmed Dahmani, Florence Coussy, Jean Marc Guinebretière, Walid Chemlali, Adrien Briaux, Sophie Chateau-Joubert, Marion Lavigne, Sophie Vacher, Samia Melaabi, Guillaume Bataillon, Adnan Naguez, Elodie Montaudon, Elisabetta Marangoni, Pierre Painsec, Fuhrmann Laetitia, Fariba Nemati, Unit of Pharmacogenomics, Department of Genetics,Laboratory of Preclinical Investigation, Department of Translational Research, Department of Medical Oncology, Institut Curie, Department of Biopathology, Università degli Studi di Roma Tor Vergata [Roma], Translational Research Department, RPPA Platform, Institut Curie Research Center, Laboratory of Preclinical Investigation, Department of Translational Research, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Unit of Pharmacogenomics, Department of Genetics, U1016, Institut National de la Santé et de la Recherche Médicale (INSERM), ProdInra, Archive Ouverte, École nationale vétérinaire - Alfort (ENVA), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Expertise en Anatomie Pathologique (APEX), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Curie [Paris], Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), AKT1, luminal androgen receptor (LAR), Triple Negative Breast Neoplasms, Targeted therapy, chemistry.chemical_compound, 0302 clinical medicine, androgen receptor, Molecular Targeted Therapy, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Triple-negative breast cancer, Phosphoinositide-3 Kinase Inhibitors, Aged, 80 and over, TOR Serine-Threonine Kinases, Middle Aged, targeted therapy, 3. Good health, [SDV] Life Sciences [q-bio], Receptors, Androgen, 030220 oncology & carcinogenesis, Benzamides, Heterografts, Female, Research Paper, Signal Transduction, Adult, Biology, 03 medical and health sciences, Cytokeratin, Breast cancer, PI3K pathway inhibitor, Nitriles, Phenylthiohydantoin, medicine, Humans, Enzalutamide, genomic alteration, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, Aged, medicine.disease, Androgen receptor, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Mutation, Cancer research
Abstract

Luminal androgen receptor (LAR) breast cancer accounts for 10% of all triple-negative breast cancers (TNBC). Anti-androgen therapy for this subtype is in development, but yields only partial clinical benefits. In this study, we aimed to characterize the genomic alterations of LAR TNBC, to analyze activation of the PI3K signaling pathway and to compare the response to PI3K pathway inhibitors with that to anti-androgen therapy in patient-derived xenografts (PDX) of LAR TNBC. Methods: Four LAR PDX models were identified, on the basis of their transcriptomic profiles, in a cohort of 57 PDX models of TNBC. The expression of AR-related genes, basal and luminal cytokeratins and EMT genes was analyzed by RT-PCR and IHC. AKT1 and PIK3CA mutations were identified by targeted NGS, and activation of the PI3K pathway was analyzed with a reverse-phase protein array. Three LAR PDXs with a PIK3CA or AKT1 mutation were treated with the AR inhibitor enzalutamide, a PI3K inhibitor, a dual PI3K-mTOR inhibitor and a mTORC1-mTORC2 inhibitor. Finally, we screened a clinical cohort of 329 TNBC for PIK3CA and AKT1 hotspot mutations. Results: LAR TNBC PDXs were significantly enriched in PIK3CA and AKT1 mutations, and had higher levels of luminal-androgen-like gene expression and a higher PI3K pathway protein activation score than other TNBC subtypes. Immunohistochemistry analysis revealed strong expression of the luminal cytokeratin CK18 and AR in three LAR PDX models. We found that mTOR and PI3K inhibitors had marked antitumor activity in vivo in PDX harboring genomic alterations of PIK3CA and AKT1 genes that did not respond to the AR antagonist enzalutamide. PIK3CA mutations were detected in more than one third of AR+ TNBC from patients (38%), and only 10% of AR-negative TNBC. Conclusion: Our results for PDX models of LAR TNBC resistant to enzalutamide indicate that PIK3CA and AKT1 are potential therapeutic targets.

Published
2020
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11. PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

Author

Pascale Mariani, André Nicolas, Leanne De Koning, Aurélie Cartier, Vesselina G. Cooke, Sergio Roman-Roman, Andrew Wylie, Didier Decaudin, Rania El Botty, Adnan Naguez, Fariba Nemati, Nathalie Cassoux, Justine Fleury, Didier Meseure, Guillaume Carita, Paul Smith, Sophie Piperno-Neumann, Elisabetta Marangoni, Mathieu Schuller, David Gentien, and Bérengère Ouine

Subjects
0301 basic medicine, Cancer Research, DNA repair, medicine.medical_treatment, Dacarbazine, Poly ADP ribose polymerase, lcsh:RC254-282, Article, Olaparib, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, uveal melanomas, Chemotherapy, Hippo signaling pathway, Chemistry, Melanoma, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, n/a, 030104 developmental biology, PARP inhibitor, Oncology, 030220 oncology & carcinogenesis, Cancer research, treatment combinations, patient-derived xenografts, medicine.drug
Abstract

Uveal melanoma (UM) remains without effective therapy at the metastatic stage, which is associated with BAP-1 (BRCA1 associated protein) mutations. However, no data on DNA repair capacities in UM are available. Here, we use UM patient-derived xenografts (PDXs) to study the therapeutic activity of the PARP inhibitor olaparib, alone or in combination. First, we show that the expression and the activity of PARP proteins is similar between the PDXs and the corresponding patient&rsquo, s tumors. In vivo experiments in the PDX models showed that olaparib was not efficient alone, but significantly increased the efficacy of dacarbazine. Finally, using reverse phase protein arrays and immunohistochemistry, we identified proteins involved in DNA repair and apoptosis as potential biomarkers predicting response to the combination of olaparib and dacarbazine. We also observed a high increase of phosphorylated YAP and TAZ proteins after dacarbazine + olaparib treatment. Our results suggest that PARP inhibition in combination with the alkylating agent dacarbazine could be of clinical interest for UM treatment. We also observe an interesting effect of dacarbazine on the Hippo pathway, confirming the importance of this pathway in UM.

Published
2019

12. A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Author

Cécile Laurent, Gaëlle Pierron, Marion Lavigne, Pierre Painsec, Ivan Bièche, Elisabetta Marangoni, Cécile Reyes, Ahmed Dahmani, Bérengère Ouine, David Gentien, Leanne De Koning, Laura Sourd, Elodie Montaudon, Anne Vincent-Salomon, Ludivine Morisset, Florence Coussy, Samia Melaabi, Franck Assayag, Thibaut Larcher, Sylvain Baulande, Elodie Girard, Céline Callens, Léa Huguet, Sophie Chateau-Joubert, Virginie Bernard, Véronique Diéras, Jean-Luc Servely, Rania El Botty, Anais Boulai, Sophie Vacher, Institut Curie, Institut Curie Research Center (Laboratory of Preclinical Investigation, Department of Translational Research), Translational Research Department, RPPA Platform, Institut Curie Research Center, Department of Biopathology, Università degli Studi di Roma Tor Vergata [Roma], Unit of Pharmacogenomics, Department of Genetics, Laboratory of Preclinical Investigation, Department of Translational Research, aboratory of Preclinical Investigation, Department of Translational Research, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Translational Research Department, Genomics Platform, U900, Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Somatic Genomics, Department of Genetics, Rt2 Lab, Genomics of Excellence (ICGex) Platform, Institut Curie Research, Department of Medical Oncology, Humanitas Centro Catanese di Oncologia, Inserm U1016, Paris Descartes University, Institut Curie [Paris], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Neuroblastoma RAS viral oncogene homolog, endocrine system, Cancer Research, Combination therapy, Class I Phosphatidylinositol 3-Kinases, [SDV]Life Sciences [q-bio], Gene Dosage, Triple Negative Breast Neoplasms, Biology, GTP Phosphohydrolases, Genetic Heterogeneity, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Animals, Humans, Gene Regulatory Networks, Molecular Targeted Therapy, Precision Medicine, Biomarker discovery, skin and connective tissue diseases, Gene, PI3K/AKT/mTOR pathway, Triple-negative breast cancer, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Membrane Proteins, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Cancer research, Immunohistochemistry, Female, Tumor Suppressor Protein p53, Neoplasm Transplantation, Signal Transduction
Abstract

Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

Published
2019
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13. Capecitabine efficacy is correlated with TYMP and RB1 expression in PDX established from triple-negative breast cancers

Author

Fabien Reyal, Ludmilla de Plater, David Gentien, Justine Fleury, Rania El-Botty, Cécile Laurent, Franck Assayag, Elisabetta Marangoni, Fariba Nemati, Sophie Château-Joubert, Sergio Roman-Roman, Ivan Bièche, Audrey Rapinat, Anne Vincent-Salomon, Jean-Luc Servely, Marick Laé, Nor Eddine Sounni, Ahmed Dahmani, Agnès Noël, Pierre Foidart, Elodie Montaudon, Didier Decaudin, Martine Piccart, Florence Coussy, Sophie Vacher, Translational Research Department, Institut Curie, Université Paris sciences et lettres (PSL), Institut Curie [Paris], BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université de Liège, Department of Pathology, Université libre de Bruxelles (ULB), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour la Recherche Contre le Cancer (ARC), Parisian Alliance of Cancer Research Institutes (PACRI), Agence Nationale de la Recherche ('Investissements d'Avenir' program) [ANR-10-EQPX-03, ANR-10-INBS-09-08], Canceropole Ile-de-France, SiRIC-Curie program-SiRIC Grant [INCa-DGOS-4654], ProdInra, Migration, École nationale vétérinaire - Alfort (ENVA), and École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, Cancer Research, Antimetabolites, Antineoplastic, endocrine system, medicine.medical_treatment, Ubiquitin-Protein Ligases, Context (language use), Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Thymidylate synthase, digestive system, Capecitabine, 03 medical and health sciences, Mice, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medicine, Neoplasm, Animals, Humans, Gene Silencing, RNA, Small Interfering, Cell Proliferation, Chemotherapy, Thymidine Phosphorylase, biology, business.industry, Gene Expression Profiling, Cancer, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Disease Models, Animal, Retinoblastoma Binding Proteins, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Immunohistochemistry, Female, Fluorouracil, business, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract

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 immunohistologic 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-naïve derived tumors, identified RB1 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. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. Clin Cancer Res; 24(11); 2605–15. ©2018 AACR.

Published
2018
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14. Metabolic response to everolimus in patient-derived triple negative breast cancer xenografts

Author

Elisabetta Marangoni, Tone Frost Bathen, Ivan Bièche, Endre Stokke, Deborah K. Hill, Rana Hatem, Leslie R. Euceda, Rania El Botty, and Siver Andreas Moestue

Subjects
0301 basic medicine, medicine.medical_treatment, Triple Negative Breast Neoplasms, Pharmacology, Biochemistry, Targeted therapy, 03 medical and health sciences, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Pharmacotherapy, Breast cancer, Medicine, Animals, Humans, Metabolomics, Everolimus, Protein kinase B, Triple-negative breast cancer, PI3K/AKT/mTOR pathway, Chemotherapy, business.industry, TOR Serine-Threonine Kinases, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Cancer research, Metabolome, Heterografts, Female, business, Proto-Oncogene Proteins c-akt, medicine.drug, Signal Transduction
Abstract

Patients with triple-negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, the response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n = 103 animals). Tumor metabolic profiles were acquired using high-resolution magic angle spinning magnetic resonance spectroscopy. Partial least-squares-discriminant analysis on relative metabolite concentrations discriminated treated xenografts from untreated controls with an accuracy of 67% (p = 0.003). Multilevel linear mixed-effects models (LMM) indicated reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR pathway inhibition. Although inherent metabolic heterogeneity between different PDX models seemed to hinder prediction of treatment response, the metabolic effects following treatment were more pronounced in responding xenografts compared to nonresponders. Additionally, the metabolic information predicted p53 mutation status, which may provide complementary insight into the interplay between PI3K signaling and other drivers of disease progression. Copyright © 2017 American Chemical Society. This is the authors' accepted and refereed manuscript to the article. Locked until 14 March 2018 due to copyright restrictions

Published
2017

15. HORMAD1 overexpression predicts response to anthracycline–cyclophosphamide and survival in triple‐negative breast cancers

Author

Rania El‐Botty, Sophie Vacher, Juliette Mainguené, Adrien Briaux, Sabrina Ibadioune, Ahmed Dahmani, Elodie Montaudon, Fariba Nemati, Léa Huguet, Laura Sourd, Ludivine Morriset, Sophie Château‐Joubert, Thierry Dubois, Virginie Maire, Rosette Lidereau, Audrey Rapinat, David Gentien, Florence Coussy, Ivan Bièche, and Elisabetta Marangoni

Subjects
AC sensitivity, biomarker, HORMAD1, TNBC, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Triple negative breast cancers (TNBCs) represent 15–20% of all breast cancers and are associated with higher recurrence and distant metastasis rate. Standard of care for early stage TNBC is anthracyclines combined with cyclophosphamide (AC) followed by taxanes, in the neo‐adjuvant or adjuvant setting. This work aimed to identify predictive biomarkers of AC response in patient‐derived xenograft (PDX) models of TNBC and to validate them in the clinical setting. By gene and protein expression analysis of 39 PDX with different responses to AC, we found that high expression of HORMAD1 was associated with better response to AC. Both gene and protein expression were associated with promoter hypomethylation. In a cohort of 526 breast cancer patients, HORMAD1 was overexpressed in 71% of TNBC. In a second cohort of 186 TNBC patients treated with AC, HORMAD1 expression was associated with longer metastasis‐free survival (MFS). In summary, HORMAD1 overexpression was predictive of an improved response to AC in PDX and is an independent prognostic factor in TNBC patients treated with AC.

Published
2023
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16. Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers

Author

Rania El-Botty, Ludivine Morriset, Elodie Montaudon, Zakia Tariq, Anne Schnitzler, Marina Bacci, Nicla Lorito, Laura Sourd, Léa Huguet, Ahmed Dahmani, Pierre Painsec, Heloise Derrien, Sophie Vacher, Julien Masliah-Planchon, Virginie Raynal, Sylvain Baulande, Thibaut Larcher, Anne Vincent-Salomon, Guillaume Dutertre, Paul Cottu, Géraldine Gentric, Fatima Mechta-Grigoriou, Scott Hutton, Keltouma Driouch, Ivan Bièche, Andrea Morandi, and Elisabetta Marangoni

Subjects
Science
Abstract

Abstract Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients’ tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.

Published
2023
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17. Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

Author

Petra ter Brugge, Sarah C. Moser, Ivan Bièche, Petra Kristel, Sabrina Ibadioune, Alexandre Eeckhoutte, Roebi de Bruijn, Eline van der Burg, Catrin Lutz, Stefano Annunziato, Julian de Ruiter, Julien Masliah Planchon, Sophie Vacher, Laura Courtois, Rania El-Botty, Ahmed Dahmani, Elodie Montaudon, Ludivine Morisset, Laura Sourd, Léa Huguet, Heloise Derrien, Fariba Nemati, Sophie Chateau-Joubert, Thibaut Larcher, Anne Salomon, Didier Decaudin, Fabien Reyal, Florence Coussy, Tatiana Popova, Jelle Wesseling, Marc-Henri Stern, Jos Jonkers, and Elisabetta Marangoni

Subjects
Science
Abstract

Homologous recombination deficiency is linked with platinum-based chemotherapy response in triple-negative breast cancer (TNBC) but methods to clinically identify these patients are lacking. Here, using patient-derived xenografts of TNBC the authors demonstrate that shallow HRD is predictive of response to platinum-based chemotherapy.

Published
2023
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18. HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast

Author

Ivan Bièche, Florence Coussy, Rania El-Botty, Sophie Vacher, Sophie Château-Joubert, Ahmed Dahmani, Elodie Montaudon, Cécile Reyes, David Gentien, Fabien Reyal, Francesco Ricci, André Nicolas, Caterina Marchio, Anne Vincent-Salomon, Marick Laé, and Elisabetta Marangoni

Subjects
Adenomyoepithelioma, HRAS, PDX, MEK inhibitor, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours’ samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.

Published
2021
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