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Published on: September 18, 2013
Preclinical Assessment of Dactinomycin in KMT2A-Rearranged Infant Acute Lymphoblastic Leukemia
Sung K Chiu1,2, Emanuela Ferrari1, Joyce Oommen1
1Leukaemia Translational Research Laboratory, WA Kids Cancer Centre, The Kids Research Institute Australia, Perth, WA 6009, Australia.
Insights
Dactinomycin showed promising in vitro activity against infant KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) but demonstrated limited efficacy in vivo, making it a low priority for clinical integration.
Area of Science:
- Pediatric Oncology
- Hematology
- Cancer Pharmacology
Background:
- Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) face poor survival and high relapse rates.
- Limited therapeutic advancements have been made for this aggressive pediatric cancer over the past two decades.
Purpose of the Study:
- To identify existing anti-cancer drugs for repurposing in infant ALL treatment.
- To evaluate the efficacy and safety of dactinomycin in preclinical models of infant ALL.
Main Methods:
- Screening of 62 anti-neoplastic drugs against eight infant ALL cell lines in vitro.
- In vitro and in vivo assessments of dactinomycin, including cytotoxicity, drug combinations, and maximum tolerated dose determination in patient-derived xenografts.
Main Results:
- Dactinomycin exhibited significant in vitro cytotoxicity against all infant ALL cell lines, with nanomolar IC50 values.
- Combination therapy showed additivity with cytarabine.
- In vivo studies established a maximum tolerated dose of 36 μg/kg, with limited survival benefit observed at 18 μg/kg.
Conclusions:
- Dactinomycin has an established safety profile in pediatric populations.
- Despite promising in vitro results, dactinomycin demonstrated limited in vivo efficacy in infant ALL models.
- Dactinomycin is not considered a priority for integration into infant ALL therapy at this time.
Abstract:
Background/Objectives: Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have high rates of relapse and poor survival compared with children. Few new therapies have been identified over the past twenty years. The aim of this study was to identify existing anti-cancer agents that have the potential to be repurposed for the treatment of infant ALL. Methods: Eight extensively characterized infant ALL cell lines were treated with 62 anti-neoplastic drugs in vitro to identify agents that exhibit significant cytotoxicity. From this screen, we selected the most effective and clinically translatable agent for further in vitro and in vivo assessment to determine the potential for use in the clinical setting. Results: Our anti-cancer drug screen revealed significant activity of dactinomycin across all infant ALL cell lines. Further in vitro testing identified low half-maximal inhibitory concentrations (IC50) across our infant ALL cell lines in the nanomolar range. Combination testing with the conventional chemotherapeutic agents currently used to treat infants with ALL demonstrated additivity with cytarabine. In vivo assessment of dactinomycin identified 36 μg/kg as the maximum tolerated dose, with unacceptable toxicities at higher dose treatment. Treatment using doses of 18 μg/kg administered either once or twice a week derived a small but significant survival benefit in patient-derived xenografts. Conclusions: Dactinomycin is extensively used for the treatment of solid tumors in children and has an acceptable safety profile when used to treat infants in this context. However, despite being readily translational and exhibiting promising in vitro cytotoxicity, dactinomycin showed limited efficacy in vivo and therefore does not represent a priority candidate for integrating into therapy for infants with ALL.
