Alexandre Gries

University Children's Hospital Zurich

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Martin Baumgartner

University Children's Hospital Zurich

Michael Grotzer

Boston Children's Hospital

Karthiga Santhana Kumar

University Children's Hospital Zurich

Christian Gaiddon

Inserm

Aldo S. Estrada‐Montaño

Universidad Nacional Autónoma de México

Alexander D. Ryabov

Carnegie Mellon University

Ronan Le Lagadec

Universidad Nacional Autónoma de México

Jessica Migliavacca

University Children's Hospital Zurich

Raymundo Marcial-Hernández

Queen Mary University of London

Carolina Torres‐Gutiérrez

Universidad Nacional Autónoma de México

Cooperative Institutions

University Children's Hospital Zurich

University of Zurich

Université de Strasbourg

Inserm

Children's Oncology Group

Centre National de la Recherche Scientifique

Universidad Nacional Autónoma de México

Institut de Recherche contre les Cancers de l’Appareil Digestif

ETH Zurich

École Polytechnique Fédérale de Lausanne

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Dibromine Promoted Transmetalation of an Organomercurial by Fe(CO)₅: Synthesis, Properties, and Cytotoxicity of Bis(2-C₆H₄-2′-py-κC,N)dicarbonyliron(II)

Organometallics (2020)

Aldo S. Estrada‐Montaño Alexandre Gries José A. Oviedo-Fortino Carolina Torres‐Gutiérrez Amira Grain-Hayton

Bis-cyclometalated iron(II) complex [Fe(κC,N-phpy)2(CO)2] (1) (phpyH = 2-phenylpyridine) has been prepared in good yield from [Fe(CO)5] and [Hg(phpy)2] in the presence of dibromine, which is unexpectedly a crucial component of the reaction mixture. It is needed for the generation of short-lived reactive intermediate [FeBr(CO)5]Br, which is actually involved in the electrophilic substitution reaction with [Hg(phpy)2]. When irradiated by visible light, compound 1 readily affords bis(2-(pyridine-2-yl)phenyl)methanone (2) and iron oxides through the insertion of CO in the Fe–C bond of the cyclometalated moiety. Structures of iron complex 1 and ketone 2 were confirmed by X-ray crystallography. Activation of [Fe(CO)5] by Br2 represents a new approach for generating an iron intermediate, which is active in transmetalation reactions. Cytotoxic activity of 1 was tested against three gastric cancer cell lines, KATO III, AGS, and NUGC3. The activity against KATO III and NUGC3 cells is moderate, while complex 1 displayed excellent cytotoxicity against AGS cells. The molecular mechanism investigation showed that the cytotoxic activity of 1 appears independent of caspase 3 and the TP53 tumor suppressor gene, suggesting an apoptotic-independent process.

Transmetalation

Moiety

10.1021/acs.organomet.0c00107

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MODL-12.Ex vivo model identifies druggable vulnerabilities in medulloblastoma

Neuro-Oncology (2022)

Alexandre Gries Davide Romanino Karthiga Santhana Kumar Ana Guerreiro Stücklin Michael Grotzer

Abstract Medulloblastoma (MB) is the most common malignant brain tumour in children and long-term sequelae in survivors caused by the harsh, non-targeted treatments is common. Current screening protocols for the detection of novel druggable vulnerabilities rely on 2D and 3D cell culture systems using established or primary tumour cells. However, these assays do neither provide the cellular, chemical and biophysical context of the tissue, nor reveal drug effects on the invasive behavior of the tumour cells. To overcome these limitations, we have established ex vivo Organotypic Cerebellum Slice Co-culture (OCSC) models for SHH and group 3 MB tumours, which provide spatio-temporal insights in the growth and dissemination behaviour of the tumour cells. OCSCs represent an excellent translational model for patient sample profiling, drug testing, and microenvironmental or explorative target identification studies in a physiologically relevant tissue context. We found that the AURKB inhibitor Barasertib (AZD-1152), which was ineffective to reduce ONS-76 cell invasion in vitro, effectively reduced tumour volume and proliferation of these SHH tumour cells in the tissue context. The AURKB inhibitor thus displays higher efficacy ex vivo, indicating an impact of the microenvironment on its functional activity. We further validated tumour suppressive activity of AURKB inhibition with Barasertib at low nanomolar concentration or with siRNA-mediated depletion of AURKB in Grp3 MB tumour cells and in primary tumour cells ex vivo, thereby confirming the therapeutic potential of AURKB inhibition against MB progression. We furthermore found that the combination of AURKB inhibition with irradiation or with the SRC inhibitor Dasatinib, lead to a near complete eradication of the tumour cells. Thus, OCSCs are a clinically relevant model where tumour material can be efficiently tested for drug sensitivities, which allowed us to identify AURKB inhibition as an effective treatment against tissue invasive MB.

Ex vivo

Druggability

10.1093/neuonc/noac079.635

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Etude des Histones Désacétylases (HDACs) comme cibles thérapeutiques dans le cancer gastrique

Alexandre Gries

En raison de l’efficience des traitements, le taux de survie globale a 5 ans des patients avec un cancer gastrique (CG) est d’environ 15%. A l’heure actuelle, il n’existe pas de stratifications des patients permettant de prescrire un protocole de traitements efficace. Durant ma these, j’ai etabli le role de HDAC4 dans la sensibilite des cellules de CG au Cisplatine. J’ai montre que cette reponse semble dependre du type de CG (intestinal ou diffus) et du statut p53 des cellules cancereuses. J’ai souligne l’interet de combiner un inhibiteur des HDACs (SAHA) avec les chimiotherapies a base de derives de platine (PDC : Cisplatine, Oxaliplatine) afin de promouvoir leurs effets cytotoxiques. De maniere interessante, j’ai observe que la reponse aux traitements combines est differente suivant le statut p53 des cellules cancereuses. Ces resultats permettent d’ouvrir de nouvelles perspectives dans l’utilisation des traitements combines PDC + SAHA dans la therapie du CG. En particulier, le facteur p53 qui est souvent mute dans les CG, pourrait etre un marqueur therapeutique pour un tel protocole de traitement.

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Repression of Aurora Kinase B Prevents Growth and Tissue Invasion in Medulloblastoma

Alexandre Gries Karthiga Santhana Kumar Fabien Kuttler Özgün Özalp Verónica Akle

10.2139/ssrn.4946664

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Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

European Journal of Inorganic Chemistry (2017)

Aldo S. Estrada‐Montaño Alexander D. Ryabov Alexandre Gries Christian Gaiddon Ronan Le Lagadec

[Fe(NCN) 2 ]PF 6 ( 1· PF 6 ) [NCHN = 1,3‐di(pyridin‐2‐yl)benzene] was readily obtained by a transmetalation reaction between [Fe 3 (CO) 12 ] and Hg(NCN)Cl followed by a metathesis reaction with KPF 6 . X‐ray diffraction, electron paramagnetic resonance spectroscopy, and cyclic voltammetry studies confirmed the proposed structure. Cytotoxic assays in human colon cancer (HCT‐15), lung cancer (SKLU), and gastric cancer (AGS, KATOIII) cells were performed, and the IC 50 data obtained for all cell lines showed that 1· PF 6 has a much higher activity than cisplatin.

Transmetalation

10.1002/ejic.201601350

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Citations (25)

Repression of Aurora kinase B prevents growth and tissue invasion in medulloblastoma

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Alexandre Gries Karthiga Santhana Kumar Fabien Kuttler Michael Grotzer Martin Baumgartner

Abstract Novel treatment strategies are required to overcome therapy-associated sequelae in survivors of pediatric medulloblastoma (MB) while maintaining therapeutic efficacy. The tissue impact on drug response in MB is not well understood and drug profiling in the physiological context of the tissue may reveal novel therapy targets. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with ex vivo organotypic cerebellum slice co-culture (OCSC), which allowed assessing tumor cell behavior in the tissue context. We screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) barasertib and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, Grp3 and Grp4 MB at nanomolar concentrations. We confirmed the necessity of AURKB for tumor growth through genetic suppression of AURKB by siRNA in the tissue context. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor dasatinib acts synergistically to repress tumor growth and invasiveness in the SHH MB cell model ONS76, but not in Grp3 MB cells. Finally, we demonstrate that pharmacological repression of AURKB in the tissue context is as effective as X-ray irradiation to repress tumor growth. Our data highlight that AURKBi is equally efficient as irradiation, suggesting that pharmacological targeting of AURKB may constitute a novel means to overcome radiotherapy limitations in patients younger than three years. Importance of the study Our data demonstrate anti-tumor activity of AURKB inhibitors in the tissue context for MB tumor cells that are in vitro resistant to the treatment. This indication of a tissue component to drug response contributes critical insights for drug response profiling for brain tumors. AURKB inhibitors barasertib and GSK-1070916 block growth and invasiveness of SHH, Grp3 and Grp4 MB tumor cells as well as primary ATRT. Importantly, AURKBi is equally efficient as irradiation. In conclusion, a tissue component contributes to sensitivity to AURKB inhibition and pharmacological targeting of AURKB may constitute a novel means to overcome radiotherapy limitations in patients younger than three years. Key points AURKB is essential for in tissue growth of MB. Inactivation of AURKB causes p53 upregulation and decreased in tissue growth and dissemination. AURKB inhibition in the tissue context is as effective as irradiation to restrict tumor cell growth.

Aurora B kinase

Aurora kinase

10.1101/2023.06.23.545872

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Citations (1)

CCDC 1920844: Experimental Crystal Structure Determination

The Cambridge Structural Database (2020)

Aldo S. Estrada‐Montaño Alexandre Gries José A. Oviedo-Fortino Carolina Torres‐Gutiérrez Amira Grain-Hayton

10.5517/ccdc.csd.cc22gsq2

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CCDC 1515206: Experimental Crystal Structure Determination

The Cambridge Structural Database (2017)

Aldo S. Estrada‐Montaño Alexander D. Ryabov Alexandre Gries Christian Gaiddon Ronan Le Lagadec

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc1mvpms

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TBIO-08. The molecular basis for rational targeting of FGFR-driven growth and invasiveness in pediatric brain tumors

Neuro-Oncology (2022)

Jessica Migliavacca Karthiga Santhana Kumar Levi Kopp Alexandre Gries Shen Yan

Abstract The oncogenic activation of receptor tyrosine kinases (RTK) promotes growth, survival and dissemination in pediatric tumors including glioma, ependymoma and medulloblastoma (MB). Direct targeting of either the RTK or of downstream kinases can effectively block tumor promoting pathway functions. However, emergence of resistance is common. We hypothesized that alternative interference strategies that target protein-protein interactions (PPIs) instead of enzymatic activities could overcome the emergence of resistance. We characterized the molecular interactions downstream of the FGFR that regulate relevant growth and invasion-promoting mechanisms in MB cells, to identify potentially druggable PPIs. We found that the FRS2 protein is an essential up-stream effector of FGFR signaling towards invasiveness. Using a proteomics approach, we furthermore identified the Striatin 3 protein as a novel oncogenic effector of the FGFR pathway downstream of FRS2, as it integrates antagonistic growth and invasion signals downstream of FGFR. Mechanistically, Striatin 3 interacts with the Ser/Thr kinase MAP4K4, couples it to the protein phosphatase 2A, and thereby inactivates growth repressing activities of MAP4K4. In parallel, Striatin 3 enables MAP4K4-mediated phosphorylation of PKC-theta and VASP, which combined are necessary to promote tissue invasion. To selectively repress pro-invasive FGFR functions, we identified and functionally validated small molecule ligands of FRS2, that prevent FRS2 activation and downstream signaling. We demonstrate efficacy of these compounds in inhibiting invasion and growth promoting activities in vitro and in vivo, and identified potential off-target activities of the ligand using a proteome-wide interaction analysis. We propose inhibition of FRS2 by a small molecular PTB domain ligand as a strategy to repress FGF signaling in FGFR-driven tumors. The development of this ligand, and the de novo design of functional analogs thereof bear promise for further pre-clinical evaluation of these structures as anti-growth promoting and anti-metastatic therapeutics applicable to FGFR-driven tumors.

10.1093/neuonc/noac079.690

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Spatial proteomics finds CD155 and Endophilin-A1 as mediators of growth and invasion in medulloblastoma

Life Science Alliance (2022)

Charles Capdeville Linda Russo David Pentón Jessica Migliavacca Milica Zecevic

The composition of the plasma membrane (PM)-associated proteome of tumor cells determines cell–cell and cell–matrix interactions and the response to environmental cues. Whether the PM-associated proteome impacts the phenotype of Medulloblastoma (MB) tumor cells and how it adapts in response to growth factor cues is poorly understood. Using a spatial proteomics approach, we observed that hepatocyte growth factor (HGF)-induced activation of the receptor tyrosine kinase c-MET in MB cells changes the abundance of transmembrane and membrane-associated proteins. The depletion of MAP4K4, a pro-migratory effector kinase downstream of c-MET, leads to a specific decrease of the adhesion and immunomodulatory receptor CD155 and of components of the fast-endophilin–mediated endocytosis (FEME) machinery in the PM-associated proteome of HGF-activated MB cells. The decreased surface expression of CD155 or of the fast-endophilin–mediated endocytosis effector endophilin-A1 reduces growth and invasiveness of MB tumor cells in the tissue context. These data thus describe a novel function of MAP4K4 in the control of the PM-associated proteome of tumor cells and identified two downstream effector mechanisms controlling proliferation and invasiveness of MB cells.

Proteome

10.26508/lsa.202201380

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Citations (9)