Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas

The survival for high-grade glioma patients is poor and the treatment may cause severe side effects. A common obstacle in the treatment is chemoresistance. To improve the quality of life and prolong survival for these patients prognostic biomarkers and new approaches for chemotherapy are needed. To this end, a strategy to evade chemoresistance was evaluated by combining chemotherapeutic drugs with agents inhibiting resistance mechanisms identified by a bioinformatic analysis (paper I). The prognostic value of 13 different proteins was analyzed in this thesis (papers II-IV). Two of them, p38 mitogen-activated protein kinase (MAPK) and protein tyrosine phosphatase non-receptor type 6 (PTPN6, also known as SHP1) were analyzed for their potential as targets in combination chemotherapy (in paper III and IV, respectively).   We found that: PTPN6 expression and methylation status may be important for survival of anaplastic glioma patients, p38 MAPK phosphorylation may be a potential negative prognostic biomarker for high-grade glioma patients and FGF2 expression may be a potential negative prognostic biomarker for proneural glioma patients. PTPN6 may be a useful target for combination chemotherapy with cisplatin, melphalan or bortezomib in high-grade gliomas. The following drug combinations; camptothecin combined with an EGFR or RAC1 inhibitor, imatinib combined with a Notch or RAC1 inhibitor, temozolomide combined with an EGFR or FAK inhibitor and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for high-grade gliomas

Synergistic effects of combining proteasome inhibitors with chemotherapeutic drugs in lung cancer cells

Abstract Background The prognosis for patients with disseminated lung cancer is poor and current treatments have limited survival benefit as resistance often occurs, and is often associated with significant toxicity. A possible strategy to improve treatment and evade chemoresistance may be to find new combinations of drugs. The aim of this study was to analyze the potential of combining proteasome inhibitors (PIs) with chemotherapeutic drugs used in the routine treatment for lung cancer patients. Results The median-effect method was applied to the Fluorometric Microculture Cytotoxicity Assay (FMCA) to evaluate effects of combining two different PIs (bortezomib and b-AP15) with clinically used chemotherapeutic drugs representing different mechanisms of action (cisplatin, gefitinib, gemcitabine and vinorelbine) in two lung cancer cell lines (one sensitive and one resistant). Proteasome inhibition in combination with cisplatin, gemcitabine or vinorelbine had synergistic effects in at least one of the tested cell lines. Furthermore, the effect of gefitinib appeared strongly potentiated by the PI in the least resistant lung cancer cell line, although the level of synergy could not be determined with the median-effect method. Conclusions Combining PIs with cisplatin, gefitinib, gemcitabine or vinorelbine show potential as new combination chemotherapy for the treatment of lung cancer

Significant off-target effects of postulated IGF-1R inhibitor picropodophyllin (PPP) in vitro

The insulin-like growth factor-1 (IGF-1) and its receptors play an important role in the transformation and progression of several malignancies. Several inhibitors of this pathway have been developed and evaluated in clinical trials, a majority of which with discouraging results and several drug candidates have been abandoned. The cyclolignan picropodophyllin (PPP) has been described as a potent and selective inhibitor of IGF-1R, and is currently investigated in clinical trials from which early reports suggest low toxicity and signs of clinical activity. In this report the cytotoxic activity of PPP and sets of standard agents were examined, compared and put in relation to the phosphorylation and expression levels of IGF-1R. The activity of PPP was unrelated to presence or spontaneous phosphorylation of IGF-1R, but correlated in all systems to activity of tubulin inhibitors. This led us to hypothesize that PPP’s effects in these cells were related to tubulin interaction rather than IGF-1R inhibition. Indeed PPP could destabilize microtubule assembly at concentrations needed to induce cytotoxicity cells, and at concentrations achievable in patients. Interestingly, PPP did also inhibit downstream signaling from tyrosine kinase receptors, including the serine/threonine kinase Akt. We could demonstrate that this surprising activity, also reported in previous reports on PPP but then attributed to IGF-1R inhibition, was associated with downregulation of the EGF receptor (EGFR). In summary, this study challenges previous reports on the cyclolignan PPP as an IGF-1R tyrosine kinase inhibitor and instead suggests that PPP targets, directly or indirectly, the microtubule network

MOESM1 of Synergistic effects of combining proteasome inhibitors with chemotherapeutic drugs in lung cancer cells

Additional file 1. SIs for each replicate of the FMCA experiments of single drugs. SI is defined as the fraction of living cells in a drug treated sample compared with an untreated sample. Each replicate is a mean of the duplicates in each experiment