Translational Medicine - Oncology
Conceptual Design: A rationale to combine targeted therapy drugs for cancer treatment based on observations of evolutionary principles of tumor development and HIV infections. In both diseases mechanisms of immune evasion and drug resistance can be compared to some extent. But only for HIV a breakthrough treatment is available, the Highly Active Antiretroviral Therapy (HAART). The principles of HAART and recent findings from cancer research are employed to build a hypothetical model for cancer treatment with a multi-drug regimen of targeted therapy drugs. As an example of this hypothesis it is proposed to combine already marketed targeted therapy drugs against VEGFRs, EGFR, CXCR4 and COX2 in an oncology trial for NSCLC patients beyond treatment (Langhammer, Oncology Reports, 2013)
Intracellular signaling pathways activated by VEGFR, EGFR, CXCR4 and E-prostanoid receptors (EP) in tumor cells and in endothelial cells shown to be involved in NSCLC tumor growth and maintenance. Recent observations indicate cross-talk mechanisms between some of these pathways leading to resistance against single agent targeted therapies alone or in combination with chemotherapeutics. Multiple inhibitions of intracellular connected pathways may overcome tumor insensitivity for targeted therapies. Targeted therapy drugs such as Sunitinib, Gefitinib, Etoricoxib and Plerixafor are clinically evaluated and FDA approved. (PGE2: prostaglandin E2).
Drug Discovery - Oncology
Expanding cancer treatment options - Identification and validation of new tumor-specific and highly functional receptor targets (Langhammer et al., Target Research Group, Bayer Schering Pharma AG, 2007).
Array Northern analysis of target mRNA and immunofluorescence of target protein in patient samples. Newly identified oncology target is exclusively upregulated in renal cell carcinomas (RCC) of 34 patients analyzed.
Translational Medicine - Virology
Answer to bioterrorist threats - Identification of new therapeutic options for treatment of poxvirus infections by applying translational medicine concepts (Langhammer et al., Antiviral Research, 2011).
In order to identify clinical relevant targets for the treatment of specific viral infections we established a standardized drug discovery process to identify, test and validate compounds and approved drugs for antiviral treatment.
Poxvirus induced EGFR signaling suppressed by the anti-tumor drug Gefitinib is dose dependent and non-toxic at millimolar concentrations. Results from plaque reduction tests of Hep2 cells infected with VACV (12.5 pfu/well) treated with a serial dilution of Gefitinib (1000µm – 0.01µm) and analyzed for (A) proliferation as indicator of cytotoxicity, (B) IC50 of plaque size inhibition, (C) dose dependent inhibition of EGFR-ERK1/2 signaling and VACV proteins by Western blot analysis (pEGFR detection was obtained from a different experiment with identical settings) and (D) dose dependent inhibition of orthopoxvirus genome replication by real-time PCR. Untreated VACV infected cells and uninfected cells are shown as controls in the right panel.
Vaccine Development against Retroviruses - First time ever showing successful vaccination by immunization with the transmembrane envelope protein of a retrovirus (Langhammer et al., Antiviral Research, 2011).
Feline Leukemia Virus (FeLV) antigen p27, provirus DNA and neutralizing activity in a non-immunized (Control) and in a p15E immunized cat (p15E-Vaccine) before and after challenge with the FeLV-A retrovirus. p27 antigen values are expressed as percentage (black line, scale indicated at left y-axis). FeLV neutralizing activity before/after virus challenge is presented in black/grey bars (scale indicated at the left y-axis). FeLV-A provirus integration is shown in copies/µl peripheral blood (dotted line, scale indicated at the right y-axis).
Vaccine Development against HIV-1 - Neutralization capacity of rat antisera induced by immunization with exploratory vaccine candidates (Langhammer et al., Robert Koch-Institute, 2006).
HIV-1 infection was measured as provirus integration by quantitative real time PCR. The mAb 2F5 was used as positive control at a concen-tration of 100µg/ml. A pool of preimmune sera was used as negative control. Provirus integration in the presence of the preimmune serum was taken as 100%. A, Sera obtained from immunizations with efficient HIV vaccine candidate I: Neutralization assay using HIV-1IIIB and C8166 cells, all sera were added at concentration 1:4. B, Neutralization assay using HIV-1IIIB and C8166 cells, serum 1.2 was added at different dilutions. C, D, Neutralization assay using the primary HIV-1 isolates SF162 (C) and Bal (D) and freshly isolated macrophages. Rat immune sera 1.2 and 1.6 were used at a dilution 1:8. E, Sera obtained from immunizations with inefficient HIV vaccine candidate II and from peptide boosts: Neutralization assay using HIV-1IIIB and C8166 cells, rat sera of animal groups 2 and 3 which differed in the boost immunization were added at a concentration 1:4.