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Cytotoxicity and Target Modulation in Pediatric Solid Tumors by the Proteasome Inhibitor Carfilzomib

Satbir Thakur1, Yibing Ruan1, Aarthi Jayanthan1

  • 1Laboratory for Pre-Clinical and Drug Discovery Studies, University of Calgary, Calgary, Alberta, Canada and Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada.

Current Cancer Drug Targets
|May 5, 2021
PubMed
Abstract

Insights

Carfilzomib (CFZ) effectively killed pediatric solid tumors in vitro. This proteasome inhibitor shows promise for treating recurrent metastatic cancers in children, warranting further clinical trials.

Area of Science:

  • Pediatric Oncology
  • Cancer Pharmacology
  • Drug Discovery

Background:

  • Recurrent metastatic solid tumors in children have poor prognoses.
  • Proteasome inhibitors demonstrate efficacy in resistant and metastatic cancer cells.
  • The therapeutic potential of Carfilzomib (CFZ) in pediatric cancers is largely unexplored.

Purpose of the Study:

  • To evaluate the efficacy of Carfilzomib (CFZ) as a proteasome inhibitor in pediatric solid tumors.
  • To determine the cytotoxic and proteasomal inhibitory effects of CFZ in vitro.
  • To investigate optimal drug scheduling and synergistic combinations for CFZ treatment.

Main Methods:

  • In vitro evaluation of CFZ cytotoxicity and proteasome inhibition across pediatric solid tumor cell lines (neuroblastoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, ATRT).
  • Drug scheduling experiments to identify effective exposure times and doses.
  • Combination studies with standard chemotherapeutic agents to assess synergistic effects.

Main Results:

  • CFZ exhibited potent cytotoxicity against all tested pediatric solid tumor cell lines (mean IC50 = 7nM).
  • Proteasome inhibition was confirmed using a cell-based assay.
  • Optimal killing was achieved with 4-8 hours/day of CFZ exposure, and it synergized with other chemotherapeutics to enhance cell death.

Conclusions:

  • Carfilzomib demonstrates significant in vitro cytotoxic activity against a range of pediatric solid tumors.
  • These findings support further investigation of CFZ, including optimized dosing, scheduling, and combination strategies, for pediatric clinical trials.
  • CFZ represents a potential therapeutic option for children with refractory solid tumors.
Keywords:
ATRTPediatric tumorscarfilzomibneuroblastomaproteasome inhibitionsarcoma.solid tumors

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