Journal article
A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers
Haematologica (Roma), v 109(11)
20 Jun 2024
PMID: 38899342
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.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.
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Details
- Title
- A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers
- Creators
- Filippo Spriano - Institute of Oncology ResearchGiulio Sartori - Institute of Oncology ResearchJacopo SgrignaniLaura Barnabei - Institute of Oncology ResearchAlberto J Arribas - SIB Swiss Institute of BioinformaticsMatilde GualaAna Maria Carrasco Del Amor - Linköping UniversityMeagan R Tomasso - Drexel UniversityChiara Tarantelli - Institute of Oncology ResearchLuciano Cascione - SIB Swiss Institute of BioinformaticsGaetanina Golino - University of Naples Federico IIMaria E Riveiro - Laboratoire Vision Action CognitionRoberta Bortolozzi - Città della Speranza FoundationAntonio Lupia - Magna Graecia UniversityFrancesco Paduano - Magna Graecia UniversitySamuel Huguet - Institut CurieKeyvan Rezai - Institut CurieAndrea Rinaldi - Institute of Oncology ResearchFrancesco Margheriti - Institute of Oncology ResearchPedro VenturaGreta GuardaGiosuè Costa - Magna Graecia UniversityRoberta Rocca - Magna Graecia UniversityAlberto FurlanLuuk M Verdonk - Leiden UniversityPaolo Innocenti - Leiden UniversityNathaniel I Martin - Leiden UniversityGiampietro Viola - Città della Speranza FoundationChristoph Driessen - Kantonsspital St. GallenEmanuele Zucca - Institute of Oncology ResearchAnastasios Stathis - Ente Ospedaliero CantonaleDigvijay GahtoryMaurits Van den NieuwboerBeat Bornhauser - University Children's Hospital ZurichStefano Alcaro - Magna Graecia UniversityFrancesco Trapasso - Magna Graecia UniversitySusana Cristobal - Linköping UniversityShae B Padrick - Drexel UniversityNatalina PazziFranco Cavalli - Institute of Oncology ResearchAndrea CavalliEugenio Gaudio - Institute of Oncology ResearchFrancesco Bertoni - Institute of Oncology Research
- Publication Details
- Haematologica (Roma), v 109(11)
- Publisher
- FERRATA STORTI FOUNDATION; PAVIA
- Number of pages
- 13
- Grant note
- Swiss National Science Foundation: 31003A_163232/1, E!2829 HEMATO-WASP FORMAS, Sweden: 310030_185185 European Union: N. 2016-02004 IKERBASQUE: 825489 Basque Foundation for ScienceBasque Government: IT-971-16 LiU MS Core facility
This study was supported by funds from the Swiss National Science Foundation (31003A_163232/1) to FB; Eurostars Project E!2829 HEMATO-WASP to DG, MvdN and FB; Swiss National Science Foundation 310030_185185 to GGu; ERA-NET Marine Biotechnology project CYANOBESITY that it is co-financed by FORMAS, Sweden grant N. 2016-02004 (SC); the GOLIATH project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement N. 825489 (to SC); IKERBASQUE, Basque Foundation for Science (to SC); Basque Government grant IT-971-16 (to SC) and LiU MS Core facility
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001371211100019
- Scopus ID
- 2-s2.0-85205083209
- Other Identifier
- 991021888215604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Hematology