Klin Padiatr 2018; 230(03): 168
DOI: 10.1055/s-0038-1644997
Top 1 Acute and chronic leukaemias
Georg Thieme Verlag KG Stuttgart · New York

Investigating novel drug combinations against patient-derived xenografts of acute lymphoblastic leukaemia

E Law
1   Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
L McKenzie
1   Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
K Szoltysek
1   Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
J Lunec
1   Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
J Irving
1   Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
J Vormoor
2   Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
,
O Heidenreich
1   Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
› Author Affiliations
Further Information

Publication History

Publication Date:
08 May 2018 (online)

Also available at
 

Introduction:

Childhood acute lymphoblastic leukaemia (ALL) responds well to conventional treatment, however there is a need to find more targeted therapies without the associated toxicities. Assessment of drug combinations is costly and time consuming in vivo. The development of an in vitro ALL patient-derived xenograft (PDX)/mesenchymal stem cell (MSC) co-culture platform allows for screening of novel drug combinations in multiple ALL subtypes.

Method:

A previously reported PDX/MSC platform was combined with a fluorescent DNA dye and microscopy to assess response to drug combinations1. Combination treatments were assessed for synergy by the Loewe method.

Results:

Treatment with dexamethasone and ABT-199 on t(17;19), t(4;11) and t(9;22) PDXs suggested synergism (Loewe synergy score 39, 52 and 59 respectively). Fluorescent microscopy revealed that the dexamethasone/ABT-199 combination had no effect on the MSC cells in the dose range tested.

Conclusion:

This high-throughput in vitro platform could reveal drugs with favourable interactions, which may be taken forward for in vivo preclinical testing for ALL patient-derived xenografts with various genomic rearrangements.

References:

Pal, D., et al., Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia. Leukemia, 2016. 30(8): p. 1691 – 700.