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|Title: ||Exploring the Pre-B receptor checkpoint as a therapeutic target in acute lymphoblasic leukaemia|
|Authors: ||Alhammer, Ali Haider Mohammed Ali.|
|Issue Date: ||2018 |
|Publisher: ||Newcastle University|
|Abstract: ||Acute lymphoblastic leukaemia (ALL) is a clonal disorder of developing lymphocytes and is the
most common malignancy in children and adolescents. While cure rates are high, treatment
is associated with significant morbidity and relapsed ALL remains one of the leading causes of
cancer‐related deaths in children. New, less toxic therapies are clearly needed for refractory
There are number of lines of evidence to suggest that ALL cells hijack component of Pre‐B cell
receptor signalling and that this dependency may be amenable to therapeutic exploitation.
There are a number of tyrosine kinase inhibitors (TKIs) targeting Pre‐BCR signalling that are
showing great promise in the clinic for other leukaemic subtypes which warrant preclinical
evaluation in childhood ALL. These include CAL‐101 (PI3K‐δ inhibitor), Ibrutinib (BTK inhibitor),
Fostamatinib (SYK inhibitor) and Dasatinib (BCR‐ABL/SRC inhibitor).
TKIs were evaluated in ALL cells, including cell lines and patient derived xenograft samples
(PDX) from 15 predominantly high risk/relapse primary ALLs. ALL cell lines were generally
resistant to all drugs but modest sensitivity was seen to the active form of fostamatinib, R406
and dasatinib in Pre‐BCR+ cells. CAL‐101 and dasatinib were shown to be cytostatic, while
ibrutinib and R406 were associated with cell cycle arrest and induction of apoptosis.
Pharmacodynamic assessments using phospho‐flow cytometry and western blotting showed
inhibition of the relevant targets at the GI50 concentrations. PDX ALL cells were generally more
sensitive than the cell lines; CAL‐101 (2 from 14 PDXs); ibrutinib (3 from 14 PDXs); R406 (6
from 15 PDXs) and dasatinib (4 from 15 PDXs). Pre‐BCR+ ALL cells were more likely to be
sensitive to dasatinib and fostamatinib. Some Pre‐BCR‐ ALL were also sensitive to some TKIs,
although predictive biomarkers remain to be established.
Significant synergism was seen after co‐treatment of the TKIs with the glucocorticoid (GC),
dexamethasone. This was most marked for the dexamethasone and dasatinib combination
and significantly potentiated G1 arrest and apoptosis in both GC sensitive and resistant ALL
cells. Synergism was associated with a significant increase in expression of the GR target, GILZ
and enhanced induction of proapoptotic BIM. In vivo preclinical confirmation of these data
may offer new therapies for refractory ALL.|
|Description: ||PhD Thesis|
|Appears in Collections:||Northern Institute for Cancer Research|
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