| Title: |
In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts |
| Authors: |
Randall, J; Evans, K; Watts, B; Smith, CM; Hughes, K; Earley, EJ; Erickson, SW; Pachter, JA; Teicher, BA; Smith, MA; Lock, RB |
| Source: |
urn:ISSN:1545-5009 ; urn:ISSN:1545-5017 ; Pediatric Blood and Cancer, 70, 8, e30398 |
| Publisher Information: |
Wiley |
| Publication Year: |
2023 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 3211 Oncology and Carcinogenesis; Cancer; Pediatric Research Initiative; Childhood Leukemia; Hematology; Biotechnology; Orphan Drug; Rare Diseases; Pediatric Cancer; 5.1 Pharmaceuticals; 3 Good Health and Well Being; Child; Humans; Animals; Mice; Heterografts; Phosphatidylinositol 3-Kinases; Inbred NOD; Leukemia; Lymphocytic; Chronic; B-Cell; Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Isoquinolines; Purines; PI3K; duvelisib; patient-derived xenografts |
| Description: |
Background: Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer-related mortality in children. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient-derived xenografts (PDXs). Procedures: Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45+ cells (%huCD45+) in the peripheral blood. Treatment commenced when the %huCD45+ reached greater than or equal to 1%, and events were predefined as %huCD45+ greater than or equal to 25% or leukemia-related morbidity. Duvelisib was administered per oral (50 mg/kg, twice daily for 28 days). Drug efficacy was assessed by event-free survival and stringent objective response measures. Results: PI3Kδ and PI3Kγ mRNA expression was significantly higher in B-lineage than T-lineage ALL PDXs (p-values |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
http://purl.org/au-research/grants/nhmrc/APP1157871; http://purl.org/au-research/grants/nhmrc/APP1059804; https://hdl.handle.net/1959.4/unsworks_83821; https://doi.org/10.1002/pbc.30398 |
| DOI: |
10.1002/pbc.30398 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_83821; https://unsworks.unsw.edu.au/bitstreams/863d55b5-9168-4a4c-9f7a-619e97ad7e4f/download; https://doi.org/10.1002/pbc.30398 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ ; free_to_read ; This is an open access article under the terrm of the Creative Commons Attribution License. |
| Accession Number: |
edsbas.AF6F889F |
| Database: |
BASE |