Haematologica (Jun 2024)
A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers
- Filippo Spriano,
- Giulio Sartori,
- Jacopo Sgrignani,
- Laura Barnabei,
- Alberto J. Arribas,
- Matilde Guala,
- Ana Maria Carrasco Del Amor,
- Meagan R. Tomasso,
- Chiara Tarantelli,
- Luciano Cascione,
- Gaetanina Golino,
- Maria E Riveiro,
- Roberta Bortolozzi,
- Antonio Lupia,
- Francesco Paduano,
- Samuel Huguet,
- Keyvan Rezai,
- Andrea Rinaldi,
- Francesco Margheriti,
- Pedro Ventura,
- Greta Guarda,
- Giosuè Costa,
- Roberta Rocca,
- Alberto Furlan,
- Luuk M. Verdonk,
- Paolo Innocenti,
- Nathaniel I. Martin,
- Giampietro Viola,
- Christoph Driessen,
- Emanuele Zucca,
- Anastasios Stathis,
- Digvijay Gahtory,
- Maurits van den Nieuwboer,
- Beat Bornhauser,
- Stefano Alcaro,
- Francesco Trapasso,
- Susana Cristobal,
- Shae B. Padrick,
- Natalina Pazzi,
- Franco Cavalli,
- Andrea Cavalli,
- Eugenio Gaudio,
- Francesco Bertoni
Affiliations
- Filippo Spriano
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Giulio Sartori
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Jacopo Sgrignani
- Institute of Research in Biomedicine, Faculty of Biomedical Sciences, USI, Bellinzona
- Laura Barnabei
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Alberto J. Arribas
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne
- Matilde Guala
- Chimete, Tortona
- Ana Maria Carrasco Del Amor
- Department of Biomedical and Clinical Sciences, Cell Biology, Medical Faculty, Linköping University, Linköping
- Meagan R. Tomasso
- Drexel University, College of Medicine, Department of Biochemistry and Molecular Biology, Philadelphia, PA
- Chiara Tarantelli
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Luciano Cascione
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne
- Gaetanina Golino
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland; Department of Pharmacy, University of Napoli Federico II, Napoli
- Maria E Riveiro
- Early Drug Development Group, Boulogne-Billancourt
- Roberta Bortolozzi
- Department of Woman’s and Child’s Health, University of Padova, Italy; Istituto di Ricerca Pediatrica IRP, Fondazione Città della Speranza, Padova
- Antonio Lupia
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy; Net4science Srl, Magna Graecia University of Catanzaro, Catanzaro
- Francesco Paduano
- University “Magna Græcia” of Catanzaro, Catanzaro, Italy; Tecnologica Research Institute and Marrelli Health, Biomedical Section, Stem Cells and Medical Genetics Units, Crotone
- Samuel Huguet
- Institut Curie, Paris
- Keyvan Rezai
- Institut Curie, Paris
- Andrea Rinaldi
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Francesco Margheriti
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Pedro Ventura
- Institute of Research in Biomedicine, Faculty of Biomedical Sciences, USI, Bellinzona
- Greta Guarda
- Institute of Research in Biomedicine, Faculty of Biomedical Sciences, USI, Bellinzona
- Giosuè Costa
- University “Magna Græcia” of Catanzaro, Catanzaro
- Roberta Rocca
- University “Magna Græcia” of Catanzaro, Catanzaro
- Alberto Furlan
- Institute of Research in Biomedicine, Faculty of Biomedical Sciences, USI, Bellinzona
- Luuk M. Verdonk
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Leiden
- Paolo Innocenti
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Leiden
- Nathaniel I. Martin
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Leiden
- Giampietro Viola
- Department of Woman’s and Child’s Health, University of Padova, Italy; Istituto di Ricerca Pediatrica IRP, Fondazione Città della Speranza, Padova
- Christoph Driessen
- Kantosspital St Gallen, St Gallen
- Emanuele Zucca
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona
- Anastasios Stathis
- Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona
- Digvijay Gahtory
- BIMINI Biotech B.V., Leiden
- Maurits van den Nieuwboer
- BIMINI Biotech B.V., Leiden
- Beat Bornhauser
- Children’s Hospital Zurich, Zurich
- Stefano Alcaro
- University “Magna Græcia” of Catanzaro, Catanzaro
- Francesco Trapasso
- University “Magna Græcia” of Catanzaro, Catanzaro
- Susana Cristobal
- Department of Biomedical and Clinical Sciences, Cell Biology, Medical Faculty, Linköping University, Linköping, Sweden; Ikerbasque, Basque Foundation for Sciences, Department of Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country
- Shae B. Padrick
- Drexel University, College of Medicine, Department of Biochemistry and Molecular Biology, Philadelphia, PA
- Natalina Pazzi
- Chimete, Tortona
- Franco Cavalli
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Andrea Cavalli
- Institute of Research in Biomedicine, Faculty of Biomedical Sciences, USI, Bellinzona
- Eugenio Gaudio
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona
- Francesco Bertoni
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona
- DOI
- https://doi.org/10.3324/haematol.2022.282672
- Journal volume & issue
-
Vol. 999,
no. 1
Abstract
Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.
