2. Academic Validation
  3. High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia

High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia

  • Biochem Pharmacol. 2023 Sep 15;115809. doi: 10.1016/j.bcp.2023.115809.
Athanasios Oikonomou 1,  Luigia Valsecchi 1,  Manuel Quadri 1,  Titus Watrin 2,  Katerina Scharov 2,  Simona Procopio 1,  Jia-Wey Tu 2,  Melina Vogt 2,  Angela Maria Savino 3,  Daniela Silvestri 1,  Maria Grazia Valsecchi 4,  Andrea Biondi 5,  Arndt Borkhardt 2,  Sanil Bhatia 2,  Giovanni Cazzaniga 6,  Grazia Fazio 1,  Michela Bardini 1,  Chiara Palmi 1
Affiliations

Affiliations

  • 1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
  • 2 Department of Paediatric Oncology, Haematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Düsseldorf, Germany.
  • 3 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; School of Medicine and Surgery, University of Milano-Bicocca, Italy.
  • 4 Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; School of Medicine and Surgery, University of Milano-Bicocca, Italy.
  • 5 Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; School of Medicine and Surgery, University of Milano-Bicocca, Italy.
  • 6 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; School of Medicine and Surgery, University of Milano-Bicocca, Italy. Electronic address: gianni.cazzaniga@asst-monza.it.
PMID: 37717691 DOI: 10.1016/j.bcp.2023.115809
Abstract

Although a great cure rate has been achieved for pediatric BCP-ALL, approximately 15% of patients do not respond to conventional chemotherapy and experience disease relapse. A major effort to improve the cure rates by treatment intensification would result in an undesirable increase in treatment-related toxicity and mortality, raising the need to identify novel therapeutic approaches. High-throughput (HTP) drug screening enables the profiling of patients' responses in vitro and allows the repurposing of compounds currently used for Other Diseases, which can be immediately available for clinical application. The aim of this study was to apply HTP drug screening to identify potentially effective compounds for the treatment of pediatric BCP-ALL patients with poor prognosis, such as patients with Down Syndrome (DS) or carrying rearrangements involving PAX5 or KMT2A/MLL genes. Patient-derived Xenografts (PDX) samples from 34 BCP-ALL patients (9 DS CRLF2r, 15 PAX5r, 10 MLLr), 7 human BCP-ALL cell lines and 14 hematopoietic healthy donor samples were screened on a semi-automated HTP drug screening platform using a 174 compound library (FDA/EMA-approved or in preclinical studies). We identified 9 compounds active against BCP-ALL (ABT-199/venetoclax, AUY922/luminespib, dexamethasone, EC144, JQ1, NVP-HSP990, paclitaxel, PF-04929113 and vincristine), but sparing normal cells. Ex vivo validations confirmed that the BCL2 inhibitor venetoclax exerts an anti-leukemic effect against all three ALL subgroups at nanomolar concentrations. Overall, this study points out the benefit of HTP screening application for drug repurposing to allow the identification of effective and clinically translatable therapeutic agents for difficult-to-treat childhood BCP-ALL subgroups.

Keywords

Down syndrome; High-throughput drug screening; MLL; PAX5; Pediatric B-cell precursor Acute Lymphoblastic Leukemia; Venetoclax.

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