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Advancement of PI3 Kinase Inhibitor Combination Therapies for PI3K-Aberrant Chordoma.
Heft Neal, Molly E; Michmerhuizen, Nicole L; Kovatch, Kevin J; Owen, John Henry J; Zhai, Jingyi; Jiang, Hui; McKean, Erin L; Prince, Mark E P; Brenner, J Chad.
Afiliación
  • Heft Neal ME; Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
  • Michmerhuizen NL; Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
  • Kovatch KJ; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, United States.
  • Owen JHJ; Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
  • Zhai J; Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
  • Jiang H; Department of Biostatistics, School of Public Heath, University of Michigan, Ann Arbor, Michigan, United States.
  • McKean EL; Department of Biostatistics, School of Public Heath, University of Michigan, Ann Arbor, Michigan, United States.
  • Prince MEP; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States.
  • Brenner JC; Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
J Neurol Surg B Skull Base ; 83(1): 87-98, 2022 Feb.
Article en En | MEDLINE | ID: mdl-35155075
ABSTRACT
Objectives Targeted inhibitors of the PI3 kinase (PI3K) pathway have shown promising but incomplete antitumor activity in preclinical chordoma models. The aim of this study is to advance methodology for a high-throughput drug screen using chordoma models to identify new combination therapies for chordoma. Study Design Present work is an in vitro study. Setting The study conducted at an academic research laboratory. Materials and Methods An in vitro study on automated high-throughput screening of chordoma cells was performed using a library of 1,406 drugs as both mono- and combination therapies with PI3K inhibitors. Combination indices were determined for dual therapies and synergistic outliers were identified as potential therapeutic agents. T (brachyury) siRNA knockdown in combination with PI3K pathway inhibition was also assessed. Results Fifty-nine combination therapies were identified as having potential therapeutic efficacy. Effective combinations included PI3K inhibitors with GSK1838705A (ALK/IGF-1R inhibitor), LY2874455 (VEGFR/FGFR inhibitor), El1 (selective Ezh2 inhibitor), and (-)-p-bromotetramisole oxalate (alkaline phosphatase inhibitor). The top ranking targets identified included ALK, PDGFR, VEGFR, aurora kinase, and BCL-2. T (brachyury) inhibition produced significant reduction in cell viability and growth; however PI3K inhibition in combination with T (brachyury) knockdown did not result in further reduction in growth and viability in vitro. Conclusion High throughput with in vitro combination screening is feasible with chordoma cells and allows for rapid identification of synergistic dual-therapies. Potential combination therapies and targetable pathways were identified. T (brachyury) knockdown produced significant reduction in cell viability, but did not show additional benefit with PI3K pathway inhibition in this model. Further in vitro and in vivo validation of these therapeutic combinations is warranted.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Neurol Surg B Skull Base Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Neurol Surg B Skull Base Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos