[Impact, and treatment possibility of chemotherapy resistance in cancer].

Chemotherapy resistance in tumours is due to complex processes and is responsible for about half of all cancer deaths. In my thesis, I have investigated multiple different resistance mechanisms, most in depth the effect of multidrug resistance (MDR) caused by expression and function of P-glycoprotein (Pgp), and the MDR-selective compounds (such as NSC297366) effectively targeting it. The mechanism was investigated using cell models with different Pgp expression.

Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases.

Aberrant activation of FMS-like tyrosine receptor kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML) in 20-30% of patients. In this study we identified a highly selective (phenylethenyl)quinazoline compound family as novel potent inhibitors of the FLT3-ITD and FLT3-D835Y kinases. Their prominent effects were confirmed by biochemical and cellular proliferation assays followed by mice xenograft studies.

Inhibition of epidermal growth factor receptor improves antitumor efficacy of vemurafenib in BRAF-mutant human melanoma in preclinical model.

Oncogenic activation of the epidermal growth factor receptor (EGFR) signaling pathway occurs in a variety of tumor types, albeit in human melanoma, the contribution of EGFR is still unclear. The potential role of EGFR was analyzed in four BRAF-mutant, one NRAS-mutant and one wild-type NRAS-BRAF-carrying human melanoma cell lines. We have tested clinically available reversible tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, irreversible EGFR-TKI pelitinib and a reversible experimental compound PD153035 on in-vitro proliferation, apoptosis, migration as well as in-vivo metastatic colonization in a spleen-liver model.

Cell type-dependent HIF1 α-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells.

Tumor hypoxia promotes neoangiogenesis and contributes to the radio- and chemotherapy resistant and aggressive phenotype of cancer cells. However, the migratory response of tumor cells and the role of small GTPases regulating the organization of cytoskeleton under hypoxic conditions have yet to be established. Accordingly, we measured the proliferation, migration, RhoA activation, the mRNA and protein levels of hypoxia inducible factor-1alpha (HIF-1α) and three small G-proteins, Rac1, cdc42 and RhoA in a panel of five human tumor cell lines under normoxic and hypoxic conditions.

[Excerpts from the collaborative lung cancer research program of Semmelweis University, the National Institute of Oncology and Korányi Institute of TB and Pulmonology (2010-2015)].

Lung cancer places a significant socio-economic burden on the Hungarian population. This overview summarizes the findings of collaborative translational lung cancer research efforts of three Hungarian flagship academic institutions, the Semmelweis University, the National Institute of Oncology and the National Koranyi Institute of TB and Pulmonology. With regards to the molecular factors regulating tumor angiogenesis, we identified the prognostic significance of apelin and erythropoietin receptor (EPOR) expression in non-small cell lung cancer (NSCLC).