Christoph W M Reuter

Publications of Christoph W M Reuter

• Modulation of anthracycline-induced cytotoxicity by targeting the prenylated proteome in myeloid leukemia cells.

  Authors: Michael A Morgan, Fredrick O Onono, H Peter Spielmann, Thangaiah Subramanian, Michaela Scherr, Letizia Venturini, Iris Dallmann, Arnold Ganser, Christoph W M Reuter

  Journal of molecular medicine (Berlin, Germany). 09/2011; 90(2):149-61.

  Deregulation of Ras/ERK signaling in myeloid leukemias makes this pathway an interesting target for drug development. Myeloid leukemia cell lines were screened for idarubicin-induced apoptosis,Deregulation of Ras/ERK signaling in myeloid leukemias makes this pathway an interesting target for drug development. Myeloid leukemia cell lines were screened for idarubicin-induced apoptosis, cell-cycle progression, cell-cycle-dependent MAP kinase kinase (MEK-1/2) activation, and Top2 expression. Cell-cycle-dependent activation of MEK/ERK signaling was blocked using farnesyltransferase inhibitor (FTI) BMS-214,662 and dual prenyltransferase inhibitor (DPI) L-778,123 to disrupt Ras signaling. Idarubicin caused a G2/M cell-cycle arrest characterized by elevated diphosphorylated MEK-1/2 and Top2α expression levels. The FTI/DPIs elicited distinct effects on Ras signaling, protein prenylation, cell cycling and apoptosis. Combining these FTI/DPIs with idarubicin synergistically inhibited proliferation of leukemia cell lines, but the L-778,123+idarubicin combination exhibited synergistic growth inhibition over a greater range of drug concentrations. Interestingly, combined FTI/DPI treatment synergistically inhibited cell proliferation, induced apoptosis and nearly completely blocked protein prenylation. Inhibition of K-Ras expression by RNA interference or blockade of its post-translational prenylation led to increased BMS-214,662-induced apoptosis. Our results suggest that nearly complete inhibition of protein prenylation using an FTI + DPI combination is the most effective method to induce apoptosis and to block anthracycline-induced activation of ERK signaling.

• A tagging-via-substrate approach to detect the farnesylated proteome using two-dimensional electrophoresis coupled with Western blotting.

  Authors: Fredrick O Onono, Michael A Morgan, H Peter Spielmann, Douglas A Andres, Thangaiah Subramanian, Arnold Ganser, Christoph W M Reuter

  Molecular & cellular proteomics : MCP. 04/2010; 9(4):742-51.

  Prenylation is a post-translational modification critical for the proper function of multiple physiologically important proteins, including small G-proteins, such as Ras. Methods allowing rapid andPrenylation is a post-translational modification critical for the proper function of multiple physiologically important proteins, including small G-proteins, such as Ras. Methods allowing rapid and selective detection of protein farnesylation and geranylgeranylation are fundamental for the understanding of prenylated protein function and for monitoring efficacy of drugs such as farnesyltransferase inhibitors (FTIs). Although the natural substrates for prenyltransferases are farnesyl pyrophosphate and geranylgeranyl pyrophosphate, farnesyltransferase has been shown to incorporate isoprenoid analogues into protein substrates. In this study, protein prenyltransferase targets were labeled using anilinogeraniol, the alcohol precursor to the unnatural farnesyl pyrophosphate analogue 8-anilinogeranyl diphosphate in a tagging-via-substrate approach. Antibodies specific for the anilinogeranyl moiety were used to detect the anilinogeranyl-modified proteins. Coupling this highly effective labeling/detection method with two-dimensional electrophoresis and subsequent Western blotting allowed simple, rapid analysis of the complex farnesylated proteome. For example, this method elucidated the differential effects induced by two chemically distinct FTIs, BMS-214,662 and L-778,123. Although both FTIs strongly inhibited farnesylation of many proteins such as Lamins, NAP1L1, N-Ras, and H-Ras, only the dual prenylation inhibitor L-778,123 blocked prenylation of Pex19, RhoB, K-Ras, Cdc42, and Rap1. This snapshot approach has significant advantages over traditional techniques, including radiolabeling, anti-farnesyl antibodies, or mass spectroscopy, and enables dynamic analysis of the farnesylated proteome.

• Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer.

  Authors: Christoph W M Reuter, Michael A Morgan, Philipp Ivanyi, Martin Fenner, Arnold Ganser, Viktor Grünwald

  World journal of urology. 03/2010; 28(3):391-8.

  There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combinationThere is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear. We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity. Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%). These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC.

• Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma.

  Authors: Christoph W M Reuter, Michael A Morgan, Viktor Grünwald, Thomas R W Herrmann, Martin Burchardt, Arnold Ganser

  World journal of urology. 04/2007; 25(1):59-72.

  Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remissionMetastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of RCC disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. Von Hippel-Lindau (VHL) gene inactivation is observed in most clear cell renal carcinoma, resulting in vascular endothelial growth factor (VEGF) over-expression and driving the malignant phenotype. This review discusses the efficacy of novel therapies targeting the VEGF receptor (VEGFR) (e.g. anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors, mTOR inhibitors), some of which were recently approved by the Food and Drug Administration/European Medicines Evaluation Agency (FDA/EMEA) and represent the new treatment standards in RCC patients.

• Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias.

  Authors: Michael A Morgan, Christoph W M Reuter

  Annals of hematology. 04/2006; 85(3):139-63.

  Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up toAlthough there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50-70% of patients who achieve a complete remission, and only 20-30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20-30% transforming to AML. The advanced age of the majority of MDS patients limits the therapeutic strategies often to supportive care. To address these shortcomings, much effort has been directed toward the development of novel treatment strategies that target the evolution and proliferation of malignant clones. Presented here is an overview of molecularly targeted therapies currently being tested in AML and MDS patients, with a focus on FMS-like tyrosine kinase 3 inhibitors, farnesyltransferase inhibitors, antiangiogenesis agents, DNA hypomethylation agents, and histone deacetylase inhibitors.

• Candida kefyr as an emerging pathogen causing nosocomial bloodstream infections in neutropenic leukemia patients.

  Authors: Christoph W M Reuter, Michael A Morgan, Franz-Christoph Bange, Florian Gunzer, Matthias Eder, Bernd Hertenstein, Arnold Ganser

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 12/2005; 41(9):1365-6.

• Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells.

  Authors: Michael A Morgan, Tarkan Sebil, Erdem Aydilek, Dietrich Peest, Arnold Ganser, Christoph W M Reuter

  British journal of haematology. 10/2005; 130(6):912-25.

  The high incidence of activating RAS mutations, coupled with accumulating evidence linking RAS to multiple myeloma (MM) pathogenesis, indicate that novel therapies utilising inhibitors of RASThe high incidence of activating RAS mutations, coupled with accumulating evidence linking RAS to multiple myeloma (MM) pathogenesis, indicate that novel therapies utilising inhibitors of RAS prenylation and signalling may be successful in the management of this disease. While preclinical studies investigating prenylation inhibitors, such as lovastatin, farnesyltransferase inhibitors (FTI) and geranylgeranyltransferase inhibitors (GGTI), have been promising, recent phase I/II clinical trials with FTI R115777 were disappointing, suggesting resistance to FTI monotherapy. To address this issue, the effects of FTI, GGTI and lovastatin alone and in combination were analysed in MM cell lines and primary cells. FTI treatment blocked H-RAS processing, but was ineffective at inhibiting K- and N-RAS prenylation because of alternative geranylgeranylation of these isoforms. However, combinations of FTI and GGTI or lovastatin were found to synergistically inhibit MM cell proliferation, migration, K- and N-RAS processing, RAS-to-mitogen-activated protein kinase signalling and to induce apoptosis. In contrast to FTI, lovastatin and some GGTI were found to cause intracellular accumulation of Rho proteins. Our results suggest that clinical efficacy of prenylation inhibitors in MM are limited by alternative prenylation of several small G-proteins, such as RhoB, K- and N-RAS. Furthermore, strategies combining FTI with GGTI or statins may provide greater efficacy in MM treatment.