Functional genomic analysis of sorafenib resistance in human FLT3-ITD-positive AML
Summary:
Flt3-internal tandem duplication (FLT3-ITD) is a recurrent mutation, which can be found in the juxtamembrane part of
the Flt3-receptor in 20-25% of all AML patients. Its expression is associated with a dismal prognosis. Sorafenib is a multikinase
and B-Raf inhibitor, which potently inhibits the kinase activity of Flt3-ITD. We have recently shown that Sorafenib (Nexavar®,
Bayer Healthcare) monotherapy induces remarkable remissions in relapsed and chemotherapy-refractory FLT3-ITD-positive AML. Unfortunately,
remissions are durable only in the context of an allogenic stem cell transplantation (allo-SCT). Resistance to sorafenib arises in
essentially all non-transplanted patients with a latency of approximately one to three months and limits treatment success with sorafenib.
This project aims to identify novel targets for the therapy of sorafenib-resistant Flt3-ITD positive acute myeloid leukemia (AML).
To achieve this, we will apply lentiviral shRNA screens to functionally identify signaling pathways in sorafenib-resistant AML samples.
We will also use whole exome sequencing of matched sensitive/resistant samples to identify and functionally validate mutations that
are involved in the development of resistance. To do so, we will rely on clinical patient material obtained from the SORMAIN trial.
The SORMAIN trial - a national multi-center phase II study, evaluating sorafenib as a maintenance drug post allo-SCT - was recently
activated by us based on the translational research results obtained in the first funding period.
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KLINISCHE FORSCHERGRUPPE 210 |
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