Article Text

PRE-CLINICAL STUDIES FOR THE IDENTIFICATION OF NOVEL THERAPEUTIC AGENTS FOR THE TREATMENT OF CNS ATYPICAL TERATOID RHABDOID TUMOR IN CHILDREN
  1. D Bernoux1,
  2. A Jayanthan1,
  3. A Incoronato1,
  4. A Narendran1
  1. 1Pediatric Oncology Department, Alberta Children’s Hospital And Tom Baker Cancer Centre, Calgary, AB, Canada

Abstract

Objective Atypical teratoid rhabdoid tumor (AT/RT) of the central nervous system is a highly malignant and difficult to treat tumor affecting mainly infants and young children. Because of the high treatment failure rate, novel treatment protocols are urgently needed for its treatment. Using an experimental model we are investigating the effects of novel targeted therapeutic agents against AT/RT tumor derived cell lines.

Methods ATRT cell lines, BT12, BT16 and KCCF1, were cultured with increasing concentrations of conventional and new chemotherapeutic agents. Cell death was determined by Alamar blue assay. Target modulation was carried out by Western blots against growth regulators and apoptosis related proteins. Drug combination studies were done by the addition of individual drugs at low concentrations with increasing concentrations of a second agent. From these data, inhibitory concentrations at 50% (IC50) and drug combination indices were calculated.

Results Our results show the induction of apoptosis and changes in signaling molecules by the multi-kinase inhibitors Sorafenib and Sunitinib at physiologically attainable concentrations. In addition, effective cell killing was also observed with the histone-deacetylase inhibitor, Apicidin and the new generation topoisomerase inhibitor, Irinotecan. Importantly, our studies show that the combination of a multi-kinase inhibitor with other anti-neoplastic agents may potentiate their anti-tumor activity.

Conclusions We present data that identify potential targeted therapeutic agents for the treatment of AT/RT in children. It is hoped that the target modulation assays presented here will provide an effective way to identify the group of children who may show responsiveness to regimens containing these agents.

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