Molecular mechanisms of cancer resistance against anti-angiogenic therapy
Summary:
Inhibitors targeting the VEGF signaling pathway have been validated as anti-angiogenic agents in
cancer patients. However, the initial antitumor and survival benefits of these drugs are transitory and are
followed by renewed tumor growth, reflecting the adaptation of tumors to anti-angiogenic therapies. Importantly,
recent evidence has implicated the induction of invasion and metastasis as a crucial component of this evasive resistance.
However, mechanistic and functional insight into anti-angiogenic resistance is limited. Our pilot studies implicate the
hypoxic activation of the EMT (epithelial-mesenchymal transition) factor ZEB2 as a key mechanism in the induction of
invasion in gliomas following inhibition of VEGF. The proposed project aims to delineate the molecular and functional
crosstalk between hypoxia signaling and EMT regulators in the acquisition of evasive resistance to anti-angiogenic treatment
strategies. We will examine the regulation of ZEB1/2 by hypoxia and will dissect the signaling pathways that link hypoxia,
ZEB1/2 and invasion/metastasis. In particular, we will assess the role of ZEB1/2 and downstream targets in promoting invasion
and metastasis following inhibition of angiogenesis, using various in vitro and in vivo tumor models. These studies are expected
to provide important insight into the mechanisms of anti-angiogenic therapy resistance and to delineate novel targets to counteract
the tumor’s evasive strategies.
Website AG Acker
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KLINISCHE FORSCHERGRUPPE 210 |
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