The effects of VEGF/VEGFR interference on cell survival and angiogenesis in AML. Preclinical and clinical studies

PhD ceremony: Ms. A.C. Weidenaar, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertaion: The effects of VEGF/VEGFR interference on cell survival and angiogenesis in AML. Preclinical and clinical studies

Promotor(s): prof. E.S.J.M. de Bont, prof. W.A. Kamps

Faculty: Medical Sciences

Acute Myeloid Leukemia (AML) is a hematological disorder that originates from bone marrow cells. Although most AML patients do respond to chemotherapy treatment, over 40% of them experience a relapse. AML is thought to be initiated and maintained by a subset of self-renewing Leukemic Stem Cells (LSC). To improve outcome, new therapeutic strategies are warranted. Vascular Endothelial Growth Factor (VEGF) is an important growth factor. In (pediatric) AML, VEGF levels are elevated and adversely associated with prognosis. Co-expression of VEGFA and its VEGF-receptors has been reported on AML cells, where VEGF/VEGFR-signaling has proliferative effects. Moreover, increased VEGFA levels are associated with a higher micro vessel density in the bone marrow of newly diagnosed AML patients.

In this thesis we investigated the potential implications of VEGF/VEGFR interference in targeting AML. We first studied the effect of PTK787/ZK 222584 (PTK/ZK), a VEGFR-inhibitor. In leukemic cell cultures (in vitro) we found that PTK/ZK reduced the number of pediatric AML-cells and LSCs. Therefore, PTK/ZK is a potentially effective approach in eradicating pediatric AML-cells and LSCs. In addition, we studied the angiogenesis in bone marrow biopsies of AML patients at diagnosis, and distinguished three morphological phenotypes. AML derived VEGF protein levels were higher in one of the phenotypes. Interestingly, the vessel morphology patterns were related to treatment outcome. These results suggest that vasculature patterns might be a useful tool to predict AML outcome. In conclusion, these studies elucidate the role of VEGFA/VEGFR signaling in AML and provide directions for future treatment strategies.