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Papers by veronica diermayr

Journal of Clinical Oncology

2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was sa... more 2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or <1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8...

XLS file - 167K, Table 1: Cell line drug sensitivity data for SB2343 and mutations in cancer gene... more XLS file - 167K, Table 1: Cell line drug sensitivity data for SB2343 and mutations in cancer genes. Table 2: Results from MANOVA analysis of cancer genes as modifiers of drug sensitivity

Supplementary Table 3 from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor ... more Supplementary Table 3 from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer

SSRN Electronic Journal, 2020

While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most... more While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration, however activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. Herein, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance and that pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.

Journal of Clinical Oncology, 2010

e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to ... more e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to target key signaling pathways in many different cancers. In general, broad-spectrum kinase inhibitor...

Blood cancer journal, 2012

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well t... more Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and t...

Molecular biology of the cell, 2005

Islet1 (Isl1) belongs to the LIM homeodomain transcription factor family. Its roles in differenti... more Islet1 (Isl1) belongs to the LIM homeodomain transcription factor family. Its roles in differentiation of motor neurons and organogenesis of pancreas and heart have been revealed. However, less is known about its regulatory mechanism and the target genes. In this study, we identified interactions between Isl1 and Janus tyrosine kinase (JAK), as well as signal transducer and activator of transcription (Stat)3, but not Stat1 and Stat5, in mammalian cells. We found that Isl1 not only forms a complex with Jak1 and Stat3 but also triggers the tyrosine phosphorylation of Jak1 and its kinase activity, thereby elevating the tyrosine phosphorylation, DNA binding activity, and target gene expression of Stat3. In vivo, the tyrosine-phosphorylated Stat3 was colocalized with Isl1 in the nucleus of the mouse motor neurons in spinal cord after nerve injury. Correspondingly, electroporation of Isl1 and Stat3 into the neural tube of chick embryos resulted in the activation of a reporter gene express...

Nucleic Acids Research, 1998

The Journal of Experimental Medicine, 1999

Over the last few years, sphingolipids have been identified as potent second messenger molecules ... more Over the last few years, sphingolipids have been identified as potent second messenger molecules modulating cell growth and activation. A newly emerging facet to this class of lipids suggests a picture where the balance between two counterregulatory lipids (as shown in the particular example of ceramide and sphingosine-1-phosphate in T lymphocyte apoptosis) determines the cell fate by setting the stage for various protein signaling cascades. Here, we provide a further example of such a decisive balance composed of the two lipids sphingosine and sphingosine-1-phosphate that determines the allergic responsiveness of mast cells. High intracellular concentrations of sphingosine act as a potent inhibitor of the immunoglobulin (Ig)E plus antigen–mediated leukotriene synthesis and cytokine production by preventing activation of the mitogen-activated protein kinase pathway. In contrast, high intracellular levels of sphingosine-1-phosphate, also secreted by allergically stimulated mast cells...

Journal of Biological Chemistry, 2005

Journal of Biological Chemistry, 2002

The transcriptional regulation of Stat proteins is controlled through their C-terminal domains, w... more The transcriptional regulation of Stat proteins is controlled through their C-terminal domains, which harbor both a tyrosine phosphorylation site, required for dimerization and subsequent nuclear translocation, and a serine phosphorylation site, required for maximum transcriptional activity. Previously, we reported that protein kinase Cδ (PKCδ) phosphorylates and interacts with Stat3 in an interleukin (IL)-6-dependent manner. In this study, we further characterized this interaction, and investigated the potential role of such an interaction. We show here that the catalytic domain of PKCδ interacts with the Src homology 2 domain and part of the adjacent C-terminal transactivation domain of Stat3. This interaction, which does not seem to involve a classical phosphotyrosine SH2-mediated binding, however, significantly enhances the interaction of Stat3 and the IL-6 receptor subunit glycoprotein (gp) 130, which is the initial step for Stat3 activation by IL-6. Expression of a dominant ne...

Journal of Biological Chemistry, 2003

Cancer Research, 2010

Kinase inhibitors have found applications in multiple oncology settings due to their ability to t... more Kinase inhibitors have found applications in multiple oncology settings due to their ability to target key signaling pathways in many different cancers. In general, the broad-spectrum kinase inhibitors have yielded better clinical outcomes than more selective ones because they block more than one pathway critical for tumor growth. We describe herein the pharmacological profile of TG02, a multi-kinase inhibitor being developed by Tragara Pharmaceuticals, which combines cell cycle regulatory and transcriptional CDK inhibition with activity against kinase targets important in the etiology of various leukemias. In vitro potency against the kinases was evaluated using recombinant enzymes with synthetic substrates. Potency on intracellular signaling pathways was assessed by Western blot analyses of the phosphorylated substrates in cell lysates. Functional potency was assessed using proliferation assays performed on human tumor cell lines as well as hematopoietic progenitors expanded from ...

bioRxiv (Cold Spring Harbor Laboratory), Feb 29, 2024

Journal of Clinical Oncology

2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was sa... more 2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or <1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8...

XLS file - 167K, Table 1: Cell line drug sensitivity data for SB2343 and mutations in cancer gene... more XLS file - 167K, Table 1: Cell line drug sensitivity data for SB2343 and mutations in cancer genes. Table 2: Results from MANOVA analysis of cancer genes as modifiers of drug sensitivity

Supplementary Table 3 from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor ... more Supplementary Table 3 from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer

SSRN Electronic Journal, 2020

While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most... more While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration, however activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. Herein, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance and that pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.

Journal of Clinical Oncology, 2010

e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to ... more e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to target key signaling pathways in many different cancers. In general, broad-spectrum kinase inhibitor...

Blood cancer journal, 2012

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well t... more Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and t...

Molecular biology of the cell, 2005

Islet1 (Isl1) belongs to the LIM homeodomain transcription factor family. Its roles in differenti... more Islet1 (Isl1) belongs to the LIM homeodomain transcription factor family. Its roles in differentiation of motor neurons and organogenesis of pancreas and heart have been revealed. However, less is known about its regulatory mechanism and the target genes. In this study, we identified interactions between Isl1 and Janus tyrosine kinase (JAK), as well as signal transducer and activator of transcription (Stat)3, but not Stat1 and Stat5, in mammalian cells. We found that Isl1 not only forms a complex with Jak1 and Stat3 but also triggers the tyrosine phosphorylation of Jak1 and its kinase activity, thereby elevating the tyrosine phosphorylation, DNA binding activity, and target gene expression of Stat3. In vivo, the tyrosine-phosphorylated Stat3 was colocalized with Isl1 in the nucleus of the mouse motor neurons in spinal cord after nerve injury. Correspondingly, electroporation of Isl1 and Stat3 into the neural tube of chick embryos resulted in the activation of a reporter gene express...

Nucleic Acids Research, 1998

The Journal of Experimental Medicine, 1999

Over the last few years, sphingolipids have been identified as potent second messenger molecules ... more Over the last few years, sphingolipids have been identified as potent second messenger molecules modulating cell growth and activation. A newly emerging facet to this class of lipids suggests a picture where the balance between two counterregulatory lipids (as shown in the particular example of ceramide and sphingosine-1-phosphate in T lymphocyte apoptosis) determines the cell fate by setting the stage for various protein signaling cascades. Here, we provide a further example of such a decisive balance composed of the two lipids sphingosine and sphingosine-1-phosphate that determines the allergic responsiveness of mast cells. High intracellular concentrations of sphingosine act as a potent inhibitor of the immunoglobulin (Ig)E plus antigen–mediated leukotriene synthesis and cytokine production by preventing activation of the mitogen-activated protein kinase pathway. In contrast, high intracellular levels of sphingosine-1-phosphate, also secreted by allergically stimulated mast cells...

Journal of Biological Chemistry, 2005

Journal of Biological Chemistry, 2002

The transcriptional regulation of Stat proteins is controlled through their C-terminal domains, w... more The transcriptional regulation of Stat proteins is controlled through their C-terminal domains, which harbor both a tyrosine phosphorylation site, required for dimerization and subsequent nuclear translocation, and a serine phosphorylation site, required for maximum transcriptional activity. Previously, we reported that protein kinase Cδ (PKCδ) phosphorylates and interacts with Stat3 in an interleukin (IL)-6-dependent manner. In this study, we further characterized this interaction, and investigated the potential role of such an interaction. We show here that the catalytic domain of PKCδ interacts with the Src homology 2 domain and part of the adjacent C-terminal transactivation domain of Stat3. This interaction, which does not seem to involve a classical phosphotyrosine SH2-mediated binding, however, significantly enhances the interaction of Stat3 and the IL-6 receptor subunit glycoprotein (gp) 130, which is the initial step for Stat3 activation by IL-6. Expression of a dominant ne...

Journal of Biological Chemistry, 2003

Cancer Research, 2010

Kinase inhibitors have found applications in multiple oncology settings due to their ability to t... more Kinase inhibitors have found applications in multiple oncology settings due to their ability to target key signaling pathways in many different cancers. In general, the broad-spectrum kinase inhibitors have yielded better clinical outcomes than more selective ones because they block more than one pathway critical for tumor growth. We describe herein the pharmacological profile of TG02, a multi-kinase inhibitor being developed by Tragara Pharmaceuticals, which combines cell cycle regulatory and transcriptional CDK inhibition with activity against kinase targets important in the etiology of various leukemias. In vitro potency against the kinases was evaluated using recombinant enzymes with synthetic substrates. Potency on intracellular signaling pathways was assessed by Western blot analyses of the phosphorylated substrates in cell lysates. Functional potency was assessed using proliferation assays performed on human tumor cell lines as well as hematopoietic progenitors expanded from ...

bioRxiv (Cold Spring Harbor Laboratory), Feb 29, 2024