BBB seminar: Kristina Viktorsson

Kristina Viktorsson
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Precision therapy of lung cancer (LC) is now emerging and this is the focus of our research where we aim to develop novel therapy and biomarkers.

Small tyrosine kinase inhibitors (TKI) directed towards mutated epidermal growth factor receptor (EGFR), induce prominent responses in non-small cell lung cancer. Yet, only 1-2% of these patients obtain complete remission, while in the majority of the cases a treatment-resistant tumor is left behind. In 30% of the mutated EGFR TKI-treated resistant cases, no other compensatory genetic alterations have been identified, illustrating the need for further identification of functional mutations with possible therapeutic implications. We have by various omic technologies identified critical pathways that control LC signaling (Stahl et al., 2009, Salim et al., 2012) and recently we have focused our efforts on the Ephrin and Eph signaling pathway, which shares multiple downstream targets with EGFR (e.g. ERK and Akt) and controls proliferation/migration of tumor cells. We have found that a signaling circuit of Ephrin B3 and multiple EphAs control LC cell proliferation, migration and invasion and also control their response to conventional radiotherapy (Stahl et al., 2011, 2013). These findings will be presented and discussed.

Unexpectedly we found a way to target another membrane receptor, the insulin growth factor receptor. In order to search for novel agents to combat LC we explored substances derived from marine organisms. We have identified compounds with clear anti-tumor potential which target insulin growth factor receptor signaling with concomitant block in proliferation and induction of apoptosis (Zovko et al., 2014). I will present how these marine compounds were identified and characterized with respect to anti-tumor action.

References:

Stahl, S., et al., (2009). Proteomics and pathway analysis identifies JNK signaling as critical for high linear energy transfer radiation-induced apoptosis in non-small lung cancer cells. Molecular & Cellular Proteomics 8:1117-29.

Salim, H., et al., (2012). miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence. British Journal of Cancer 107:1361-73.

Stahl, S., et al., (2011). Phosphoproteomic profiling of NSCLC cells reveals that Ephrin B3 regulates pro-survival signaling through Akt1-mediated phosphorylation of the EphA2 receptor. Journal of Proteome Research 10:2566-78.

Stahl, S., et al., (2013). Inhibition of Ephrin B3-mediated survival signaling contributes to increased cell death response of non-small cell lung carcinoma cells after combined treatment with ionizing radiation and PKC 412. Cell Death & Disease 4:e454.

Zovko A, et al., (2014). Marine sponge Cribrochalina vasculum compounds activate intrinsic apoptotic signaling and inhibit growth factor signaling cascades in non-small cell lung carcinoma. Molecular Cancer Therapeutics 13:2941-54.

Chairperson: Reidun Æsøy, Department of Biomedicine