Myeloproliferative Syndrome Clinical Trial
Official title:
Efficacy of Heat-shock Protein (HSP) Inhibitors in Myeloproliferative Syndromes (MPS): Fundamental Observational in Vitro Study Using Samples From a Collection
Heat-shock proteins (HSP) have been very highly conserved throughout the evolution of
species and are characterized by their chaperone function, thanks to their ability to
prevent aggregation and to promote the renaturation/break down of damaged proteins. Among
other targets, they also chaperone JAK2, a key step that is deregulated in signalling in
myeloproliferative syndromes (MPS) because of the JAK2V617F mutation. These HSP also have a
potent cytoprotective action through their multiples inhibiting effects on apoptotic
processes.
Little is known about levels of HSP expression, in particular for HSP70 and HSP27, in MPS
cells.
However, in vitro studies of different cell models have shown the interest of HSP90
inhibitors in slowing cell proliferation in MPS. These results have been confirmed in animal
models with results in terms of blood counts and overall survival. In addition, it seems
that the V617F mutated form of JAK2 is more sensitive than the wild-type to HSP90
inhibitors. Finally, inhibitors of HSP90 remain efficacious with regard to the inhibition of
cell growth, even in cases of resistance to JAK2 inhibitors. Nonetheless, HSP90 inhibitors
are known to stimulate the expression of other HSP, notably HSP27 and HSP70, which are,
through their properties, tumorigenic and could lead to an escape phenomenon. Thus the
combined use of several HSP inhibitors could be beneficial, and eventually present
synergistic effects on the inhibition of tumour processes.
n/a
Time Perspective: Retrospective
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