Nikolas von Bubnoff - Academia.edu (original) (raw)

Papers by Nikolas von Bubnoff

Research paper thumbnail of Endothelial-like cells expanded from CD34+ blood cells improve left ventricular function after experimental myocardial infarction

The FASEB Journal, 2005

Mobilization and recruitment of endothelial progenitor cells (EPC) contributes to vasculogenesis ... more Mobilization and recruitment of endothelial progenitor cells (EPC) contributes to vasculogenesis in vivo. So far, applications for cell therapy are limited by the number of available cells.

Research paper thumbnail of Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back

Leukemia, 2003

Cancer research within the last decades elucidated signaling pathways and identified genes and pr... more Cancer research within the last decades elucidated signaling pathways and identified genes and proteins that lead or contribute to malignant transformation of a cell. Discovery of the Bcr-Abl oncoprotein as the molecular abnormality causing chronic myeloid leukemia (CML) paved the way for the development of a targeted anticancer therapy. The substantial activity of imatinib mesylate (STI571, Glivec) in CML and Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) changed the therapeutic approach to Ph+ leukemia and rang the bell for a new era of anticancer treatment. However, when the phenomenon of relapse occurred despite continued imatinib treatment, we had to learn the lesson that imatinib can select for a resistant disease clone. If such a clone still depends on Bcr-Abl, it either carries a BCR-ABL point mutation that prevents binding of the drug or expresses the fusion protein at high levels. Alternatively, leukemia cells that harbor secondary genetic alterations resulting in Bcr-Abl-independent proliferation are selected for their growth advantage in the presence of imatinib. Point mutations in the BCR-ABL kinase domain prevent binding of imatinib but still allow binding of ATP, thus retaining Bcr-Abl kinase activity. Mutated BCR-ABL is frequently detected in cases of imatinib-resistant Ph+ leukemia and therefore represents the main challenge for the investigation of alternative strategies to either overcome resistance or to prevent the emergence of a resistant leukemic clone.

Research paper thumbnail of FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro

Cancer Research, Apr 1, 2009

FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown activity in the treatment of acute myelog... more FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown activity in the treatment of acute myelogenous leukemia (AML). Secondary mutations in target kinases can cause clinical resistance to therapeutic kinase inhibition. We have previously shown that sensitivity toward tyrosine kinase inhibitors varies between different activating FLT3 mutations. We therefore intended to determine whether different FLT3 inhibitors would produce distinct profiles of secondary, FLT3 resistance mutations. Using a cell-based screening approach, we generated FLT3-internal tandem duplication (ITD)expressing cell lines resistant to the FLT3 inhibitors SU5614, PKC412, and sorafenib. Interestingly, the profile of resistance mutations emerging with SU5614 was limited to exchanges in the second part of the kinase domain (TK2) with exchanges of D835 predominating. In contrast, PKC412 exclusively produced mutations within tyrosine kinase domain 1 (TK1) at position N676. A mutation at N676 recently has been reported in a case of PKC412-resistant AML. TK1 mutations exhibited a differential response to SU5614, sorafenib, and sunitinib but strongly impaired response to PKC412. TK2 exchanges identified with SU5614 were sensitive to PKC412, sunitinib, or sorafenib, with the exception of Y842D, which caused a strong resistance to sorafenib. Of note, sorafenib also produced a highly distinct profile of resistance mutations with no overlap to SU5614 or PKC412, including F691L in TK1 and exchanges at position Y842 of TK2. Thus, different FLT3 kinase inhibitors generate distinct, nonoverlapping resistance profiles. This is in contrast to Bcr-Abl kinase inhibitors such as imatinib, nilotinib, and dasatinib, which display overlapping resistance profiles. Therefore, combinations of FLT3 inhibitors may be useful to prevent FLT3 resistance mutations in the setting of FLT3-ITDpositive AML.

Research paper thumbnail of Methods and Compositions for Diagnosing Gastrointestinal Stromal Tumors

Research paper thumbnail of A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: implications for clinical resistance in targeted cancer treatment

Cell Cycle, Apr 1, 2005

The discovery of tyrosine kinases that, once deregulated, can cause malignancy, allowed the devel... more The discovery of tyrosine kinases that, once deregulated, can cause malignancy, allowed the development of specifically acting anti-cancer compounds. In chronic myeloid leukaemia (CML), the Bcr-Abl kinase inhibitor imatinib (STI571, Gleevec) induces impressive response rates. However, resistance occurs especially in advanced phase CML and Ph + ALL, primarily as a consequence of point mutations within the Bcr-Abl kinase domain that prevent imatinib from binding. To overcome imatinib resistance, alternative Abl kinase inhibitors are finding their way into clinical trials. However, it is likely that resistance to second-generation compounds will occur as well. Therefore, it will be critical to determine specific resistance profiles for each particular compound. We recently developed a cell-based screening strategy that allows one to predict the pattern and relative abundance of Bcr-Abl resistance mutations emerging in the presence of imatinib or an alternative Abl-kinase inhibitor. Using this strategy, the findings in inhibitor resistant sublines reflect observations made in CML patients with imatinib resistance, including Bcr-Abl mutations, amplification of the Bcr-Abl gene, and overexpression of the Bcr-Abl protein. We here provide a detailed methodological description, and discuss the implications of this strategy for different clinically relevant oncogenic tyrosine kinases.

Research paper thumbnail of Identification Of a Novel Mode Of Kinase Inhibitor Resistance In JAK2: JAK2 Inhibitor Resistance Is Mediated By The Generation Of 45-Kda JAK2 Variant Which Alters The Kinase Domain Structure

Research paper thumbnail of Sensitive and accurate quantification of JAK2 V617F mutation in chronic myeloproliferative neoplasms by droplet digital PCR

Annals of Hematology, 2016

The JAK2 V617F mutation can be detected with a high frequency in patients with myeloproliferative... more The JAK2 V617F mutation can be detected with a high frequency in patients with myeloproliferative neoplasms (MPN). MPN treatment efficiency can be assessed by JAK2 V617F quantification. Real-time quantitative PCR (qPCR) is widely used for JAK2 V617F quantification. Emerging alternative technologies like digital droplet PCR (ddPCR) have been described to overcome inherent qPCR limitations. The purpose of this study was to evaluate the utility of ddPCR for JAK2 V617F quantification in patient samples with MPN. Sensitivity and specificity were established by using DNA artificial mixtures. In addition, 101 samples from 59 patients were evaluated for JAK2 V617F mutation. Limit of detection was 0.01 % for both qPCR and ddPCR. The JAK2 V617F mutation was detected in 43 out of 59 patients by both PCR platforms. However, in 14 % of the samples, JAK2 V617F mutation was detected only with ddPCR. This 14 % of discrepant samples were from patients shortly after allogeneic stem cell transplantation. Percentage of JAK2 V617F mutation measured by qPCR and ddPCR in clinical samples showed a high degree of correlation (Spearman r: 0.9637 p < 0.001) and an excellent agreement assessed by Bland-Altman analysis. In conclusion, ddPCR is a suitable, precise, and sensitive method for quantification of the JAK 2 V617F mutation.

Research paper thumbnail of A cell-based screening strategy predicts Bcr-Abl mutations that cause resistance toward the second-generation Abl kinase inhibitor AMN107

Cancer Research, May 1, 2005

Research paper thumbnail of Ein alternativer Abl-Kinase-Inhibitor hemmt Imatinib-Resistenzmutationen des Bcr-Abl-Onkogens

Deut Med Wochenschr, 2004

Research paper thumbnail of Sorafenib Promotes Graft-Versus-Leukemia Activity in Mice and Humans through IL-15 Production in Leukemia Cells

Biology of Blood and Marrow Transplantation, 2016

Research paper thumbnail of Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia

Research paper thumbnail of inhibitor identifies the mutation pattern for PD166326, an alternative Abl kinase A cell-based screen for resistance of Bcr-Abl-positive leukemia

Research paper thumbnail of BCR-ABL P-Loop Deletion Detected in Imatinib-Resistant CML Patients Corresponds to Splice Variant Associated with L248V Point Mutation, Retains BCR-ABL Kinase Activity, and Responds to Dasatinib Treatment

Ash Annual Meeting Abstracts, Nov 1, 2006

Research paper thumbnail of Aurora kinases A and B are Myc targets essential for maintenance of the malignant state

... Technology)) (Jonas Nilsson). Doherty, Joanne R (Department of Cancer Biology, The Scripps Re... more ... Technology)) (Jonas Nilsson). Doherty, Joanne R (Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA) (John Cleveland). Rudelius, Martina (Department of Pathology, Technische Universität München, Munich, Germany). Buck, ...

Research paper thumbnail of Ruxolitinib

Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer, 2014

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of ... more Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of JAK1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis, which is characterized, biologically, by the activation of the JAK-STAT pathway and, clinically, by bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of myelofibrosis patients, and it may also have a favorable effect on survival. Treatment response apparently does not depend on the presence of a JAK2 V617F mutation. The predominant toxicities are thrombocytopenia and anemia. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently studied in myelofibrosis or other immuno-inflammatory diseases.

Research paper thumbnail of Chronic myelogenous leukemia: treatment and monitoring

Deutsches Ärzteblatt international, 2010

The treatment options for bcr-abl positive chronic myelogenous leukemia (CML) include chemotherap... more The treatment options for bcr-abl positive chronic myelogenous leukemia (CML) include chemotherapy, immune therapy, allogeneic stem cell transplantation, and molecular therapy. The tyrosine kinase inhibitor imatinib was approved for the treatment of CML in 2002. Data from clinical trials allow a comparison of treatment options. The literature on the treatment and monitoring of CML was selectively reviewed. A total of 94 original articles were analyzed, along with the recommendations of an international expert committee and the medical societies. This review is current as of November 2009. In a clinical phase 3 trial of imatinib treatment for patients in the chronic phase of CML, the rates of progression-free and overall survival at 6 years were 93% and 88%, respectively. Thus, imatinib is clearly superior to interferon-alpha, hydroxyurea, and busulfan with respect to survival. Allogeneic stem-cell transplantation is only a fall back option because of transplantation-associated morta...

Research paper thumbnail of Pitfalls in imaging Hodgkin's disease with computed tomography and positron emission tomography using fluorine-18-fluorodeoxyglucose

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2001

We report on a patient with Hodgkin's disease who presented with hypodense splenic lesions an... more We report on a patient with Hodgkin's disease who presented with hypodense splenic lesions and corresponding increased glucose metabolism in FDG-PET imaging, four months after completion of initial treatment, suggestive of early relapse. Serological testing for toxoplasma gondii, however, showed evidence of a recently reactivated or newly acquired infection. Three weeks after immediate antibiotic treatment with Daraprime and Sulfadiazin, the splenic lesions had completely resolved. Additionally, serological titers for toxoplasma gondii were normalized and whole body FDG-PET imaging showed no metabolic activity. Although the positive predictive value of PET imaging to indicate lymphoma is reported to be higher than CT, hypermetabolic lesions are not specific for malignant tissue. Whereas benign tumors typically show low glucose metabolism, activated granulocytes and macrophages may display significantly increased glucose consumption. In conclusion, our case report shows that alth...

Research paper thumbnail of Inhibition of Aurora Kinase B Is Important for Biologic Activity of the Dual Inhibitors of BCR-ABL and Aurora Kinases R763/AS703569 and PHA-739358 in BCR-ABL Transformed Cells

PLoS ONE, 2014

ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard... more ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/ AS703569 in Ba/F3-cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.

Research paper thumbnail of Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors

Cancer research, 2003

Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type ... more Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type kinase inhibitor, proved to be active in Philadelphia-positive leukemias. Resistance toward imatinib develops frequently in advanced-stage Philadelphia-positive leukemia, and is even observed in chronic-phase chronic myelogenous leukemia. Point mutations within the BCR-ABL kinase domain emerged as a major mechanism of resistance toward imatinib. Mutations occur at positions that determine specific contacts of imatinib to the ATP-binding site. We aimed to examine whether pyrido-pyrimidine-type kinase inhibitors were capable of inhibiting both wild-type and mutant forms of BCR-ABL. We screened 13 different pyrido-pyrimidine with cells expressing wild-type and mutant BCR-ABL. All of the substances specifically suppressed the Bcr-Abl dependent phenotype and inhibited Bcr-Abl kinase activity with higher potency than imatinib. Two of the most active compounds were PD166326 and SKI DV-M016. Int...

Research paper thumbnail of Chronic myelogenous leukemia (CML)

Chronic Myeloid Neoplasias and Clonal Overlap Syndromes, 2010

Page 1. 5 Chronic Myeloid Leukemia (CML) Nikolas von Bubnoff, Lisa Pleyer, Daniel Neureiter, Vict... more Page 1. 5 Chronic Myeloid Leukemia (CML) Nikolas von Bubnoff, Lisa Pleyer, Daniel Neureiter, Victoria Faber, and Justus Duyster Contents 5.1 Introduction ..... 118 5.2 Epidemiology ..... ...

Research paper thumbnail of Endothelial-like cells expanded from CD34+ blood cells improve left ventricular function after experimental myocardial infarction

The FASEB Journal, 2005

Mobilization and recruitment of endothelial progenitor cells (EPC) contributes to vasculogenesis ... more Mobilization and recruitment of endothelial progenitor cells (EPC) contributes to vasculogenesis in vivo. So far, applications for cell therapy are limited by the number of available cells.

Research paper thumbnail of Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back

Leukemia, 2003

Cancer research within the last decades elucidated signaling pathways and identified genes and pr... more Cancer research within the last decades elucidated signaling pathways and identified genes and proteins that lead or contribute to malignant transformation of a cell. Discovery of the Bcr-Abl oncoprotein as the molecular abnormality causing chronic myeloid leukemia (CML) paved the way for the development of a targeted anticancer therapy. The substantial activity of imatinib mesylate (STI571, Glivec) in CML and Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) changed the therapeutic approach to Ph+ leukemia and rang the bell for a new era of anticancer treatment. However, when the phenomenon of relapse occurred despite continued imatinib treatment, we had to learn the lesson that imatinib can select for a resistant disease clone. If such a clone still depends on Bcr-Abl, it either carries a BCR-ABL point mutation that prevents binding of the drug or expresses the fusion protein at high levels. Alternatively, leukemia cells that harbor secondary genetic alterations resulting in Bcr-Abl-independent proliferation are selected for their growth advantage in the presence of imatinib. Point mutations in the BCR-ABL kinase domain prevent binding of imatinib but still allow binding of ATP, thus retaining Bcr-Abl kinase activity. Mutated BCR-ABL is frequently detected in cases of imatinib-resistant Ph+ leukemia and therefore represents the main challenge for the investigation of alternative strategies to either overcome resistance or to prevent the emergence of a resistant leukemic clone.

Research paper thumbnail of FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro

Cancer Research, Apr 1, 2009

FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown activity in the treatment of acute myelog... more FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown activity in the treatment of acute myelogenous leukemia (AML). Secondary mutations in target kinases can cause clinical resistance to therapeutic kinase inhibition. We have previously shown that sensitivity toward tyrosine kinase inhibitors varies between different activating FLT3 mutations. We therefore intended to determine whether different FLT3 inhibitors would produce distinct profiles of secondary, FLT3 resistance mutations. Using a cell-based screening approach, we generated FLT3-internal tandem duplication (ITD)expressing cell lines resistant to the FLT3 inhibitors SU5614, PKC412, and sorafenib. Interestingly, the profile of resistance mutations emerging with SU5614 was limited to exchanges in the second part of the kinase domain (TK2) with exchanges of D835 predominating. In contrast, PKC412 exclusively produced mutations within tyrosine kinase domain 1 (TK1) at position N676. A mutation at N676 recently has been reported in a case of PKC412-resistant AML. TK1 mutations exhibited a differential response to SU5614, sorafenib, and sunitinib but strongly impaired response to PKC412. TK2 exchanges identified with SU5614 were sensitive to PKC412, sunitinib, or sorafenib, with the exception of Y842D, which caused a strong resistance to sorafenib. Of note, sorafenib also produced a highly distinct profile of resistance mutations with no overlap to SU5614 or PKC412, including F691L in TK1 and exchanges at position Y842 of TK2. Thus, different FLT3 kinase inhibitors generate distinct, nonoverlapping resistance profiles. This is in contrast to Bcr-Abl kinase inhibitors such as imatinib, nilotinib, and dasatinib, which display overlapping resistance profiles. Therefore, combinations of FLT3 inhibitors may be useful to prevent FLT3 resistance mutations in the setting of FLT3-ITDpositive AML.

Research paper thumbnail of Methods and Compositions for Diagnosing Gastrointestinal Stromal Tumors

Research paper thumbnail of A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: implications for clinical resistance in targeted cancer treatment

Cell Cycle, Apr 1, 2005

The discovery of tyrosine kinases that, once deregulated, can cause malignancy, allowed the devel... more The discovery of tyrosine kinases that, once deregulated, can cause malignancy, allowed the development of specifically acting anti-cancer compounds. In chronic myeloid leukaemia (CML), the Bcr-Abl kinase inhibitor imatinib (STI571, Gleevec) induces impressive response rates. However, resistance occurs especially in advanced phase CML and Ph + ALL, primarily as a consequence of point mutations within the Bcr-Abl kinase domain that prevent imatinib from binding. To overcome imatinib resistance, alternative Abl kinase inhibitors are finding their way into clinical trials. However, it is likely that resistance to second-generation compounds will occur as well. Therefore, it will be critical to determine specific resistance profiles for each particular compound. We recently developed a cell-based screening strategy that allows one to predict the pattern and relative abundance of Bcr-Abl resistance mutations emerging in the presence of imatinib or an alternative Abl-kinase inhibitor. Using this strategy, the findings in inhibitor resistant sublines reflect observations made in CML patients with imatinib resistance, including Bcr-Abl mutations, amplification of the Bcr-Abl gene, and overexpression of the Bcr-Abl protein. We here provide a detailed methodological description, and discuss the implications of this strategy for different clinically relevant oncogenic tyrosine kinases.

Research paper thumbnail of Identification Of a Novel Mode Of Kinase Inhibitor Resistance In JAK2: JAK2 Inhibitor Resistance Is Mediated By The Generation Of 45-Kda JAK2 Variant Which Alters The Kinase Domain Structure

Research paper thumbnail of Sensitive and accurate quantification of JAK2 V617F mutation in chronic myeloproliferative neoplasms by droplet digital PCR

Annals of Hematology, 2016

The JAK2 V617F mutation can be detected with a high frequency in patients with myeloproliferative... more The JAK2 V617F mutation can be detected with a high frequency in patients with myeloproliferative neoplasms (MPN). MPN treatment efficiency can be assessed by JAK2 V617F quantification. Real-time quantitative PCR (qPCR) is widely used for JAK2 V617F quantification. Emerging alternative technologies like digital droplet PCR (ddPCR) have been described to overcome inherent qPCR limitations. The purpose of this study was to evaluate the utility of ddPCR for JAK2 V617F quantification in patient samples with MPN. Sensitivity and specificity were established by using DNA artificial mixtures. In addition, 101 samples from 59 patients were evaluated for JAK2 V617F mutation. Limit of detection was 0.01 % for both qPCR and ddPCR. The JAK2 V617F mutation was detected in 43 out of 59 patients by both PCR platforms. However, in 14 % of the samples, JAK2 V617F mutation was detected only with ddPCR. This 14 % of discrepant samples were from patients shortly after allogeneic stem cell transplantation. Percentage of JAK2 V617F mutation measured by qPCR and ddPCR in clinical samples showed a high degree of correlation (Spearman r: 0.9637 p < 0.001) and an excellent agreement assessed by Bland-Altman analysis. In conclusion, ddPCR is a suitable, precise, and sensitive method for quantification of the JAK 2 V617F mutation.

Research paper thumbnail of A cell-based screening strategy predicts Bcr-Abl mutations that cause resistance toward the second-generation Abl kinase inhibitor AMN107

Cancer Research, May 1, 2005

Research paper thumbnail of Ein alternativer Abl-Kinase-Inhibitor hemmt Imatinib-Resistenzmutationen des Bcr-Abl-Onkogens

Deut Med Wochenschr, 2004

Research paper thumbnail of Sorafenib Promotes Graft-Versus-Leukemia Activity in Mice and Humans through IL-15 Production in Leukemia Cells

Biology of Blood and Marrow Transplantation, 2016

Research paper thumbnail of Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia

Research paper thumbnail of inhibitor identifies the mutation pattern for PD166326, an alternative Abl kinase A cell-based screen for resistance of Bcr-Abl-positive leukemia

Research paper thumbnail of BCR-ABL P-Loop Deletion Detected in Imatinib-Resistant CML Patients Corresponds to Splice Variant Associated with L248V Point Mutation, Retains BCR-ABL Kinase Activity, and Responds to Dasatinib Treatment

Ash Annual Meeting Abstracts, Nov 1, 2006

Research paper thumbnail of Aurora kinases A and B are Myc targets essential for maintenance of the malignant state

... Technology)) (Jonas Nilsson). Doherty, Joanne R (Department of Cancer Biology, The Scripps Re... more ... Technology)) (Jonas Nilsson). Doherty, Joanne R (Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA) (John Cleveland). Rudelius, Martina (Department of Pathology, Technische Universität München, Munich, Germany). Buck, ...

Research paper thumbnail of Ruxolitinib

Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer, 2014

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of ... more Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of JAK1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis, which is characterized, biologically, by the activation of the JAK-STAT pathway and, clinically, by bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of myelofibrosis patients, and it may also have a favorable effect on survival. Treatment response apparently does not depend on the presence of a JAK2 V617F mutation. The predominant toxicities are thrombocytopenia and anemia. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently studied in myelofibrosis or other immuno-inflammatory diseases.

Research paper thumbnail of Chronic myelogenous leukemia: treatment and monitoring

Deutsches Ärzteblatt international, 2010

The treatment options for bcr-abl positive chronic myelogenous leukemia (CML) include chemotherap... more The treatment options for bcr-abl positive chronic myelogenous leukemia (CML) include chemotherapy, immune therapy, allogeneic stem cell transplantation, and molecular therapy. The tyrosine kinase inhibitor imatinib was approved for the treatment of CML in 2002. Data from clinical trials allow a comparison of treatment options. The literature on the treatment and monitoring of CML was selectively reviewed. A total of 94 original articles were analyzed, along with the recommendations of an international expert committee and the medical societies. This review is current as of November 2009. In a clinical phase 3 trial of imatinib treatment for patients in the chronic phase of CML, the rates of progression-free and overall survival at 6 years were 93% and 88%, respectively. Thus, imatinib is clearly superior to interferon-alpha, hydroxyurea, and busulfan with respect to survival. Allogeneic stem-cell transplantation is only a fall back option because of transplantation-associated morta...

Research paper thumbnail of Pitfalls in imaging Hodgkin's disease with computed tomography and positron emission tomography using fluorine-18-fluorodeoxyglucose

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2001

We report on a patient with Hodgkin's disease who presented with hypodense splenic lesions an... more We report on a patient with Hodgkin's disease who presented with hypodense splenic lesions and corresponding increased glucose metabolism in FDG-PET imaging, four months after completion of initial treatment, suggestive of early relapse. Serological testing for toxoplasma gondii, however, showed evidence of a recently reactivated or newly acquired infection. Three weeks after immediate antibiotic treatment with Daraprime and Sulfadiazin, the splenic lesions had completely resolved. Additionally, serological titers for toxoplasma gondii were normalized and whole body FDG-PET imaging showed no metabolic activity. Although the positive predictive value of PET imaging to indicate lymphoma is reported to be higher than CT, hypermetabolic lesions are not specific for malignant tissue. Whereas benign tumors typically show low glucose metabolism, activated granulocytes and macrophages may display significantly increased glucose consumption. In conclusion, our case report shows that alth...

Research paper thumbnail of Inhibition of Aurora Kinase B Is Important for Biologic Activity of the Dual Inhibitors of BCR-ABL and Aurora Kinases R763/AS703569 and PHA-739358 in BCR-ABL Transformed Cells

PLoS ONE, 2014

ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard... more ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/ AS703569 in Ba/F3-cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.

Research paper thumbnail of Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors

Cancer research, 2003

Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type ... more Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type kinase inhibitor, proved to be active in Philadelphia-positive leukemias. Resistance toward imatinib develops frequently in advanced-stage Philadelphia-positive leukemia, and is even observed in chronic-phase chronic myelogenous leukemia. Point mutations within the BCR-ABL kinase domain emerged as a major mechanism of resistance toward imatinib. Mutations occur at positions that determine specific contacts of imatinib to the ATP-binding site. We aimed to examine whether pyrido-pyrimidine-type kinase inhibitors were capable of inhibiting both wild-type and mutant forms of BCR-ABL. We screened 13 different pyrido-pyrimidine with cells expressing wild-type and mutant BCR-ABL. All of the substances specifically suppressed the Bcr-Abl dependent phenotype and inhibited Bcr-Abl kinase activity with higher potency than imatinib. Two of the most active compounds were PD166326 and SKI DV-M016. Int...

Research paper thumbnail of Chronic myelogenous leukemia (CML)

Chronic Myeloid Neoplasias and Clonal Overlap Syndromes, 2010

Page 1. 5 Chronic Myeloid Leukemia (CML) Nikolas von Bubnoff, Lisa Pleyer, Daniel Neureiter, Vict... more Page 1. 5 Chronic Myeloid Leukemia (CML) Nikolas von Bubnoff, Lisa Pleyer, Daniel Neureiter, Victoria Faber, and Justus Duyster Contents 5.1 Introduction ..... 118 5.2 Epidemiology ..... ...