Lukas Amler - Academia.edu (original) (raw)

Papers by Lukas Amler

Research paper thumbnail of Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Nature Medicine, 2007

Apo2L/TRAIL stimulates cancer cell death through the proapoptotic receptors DR4 and DR5, but the ... more Apo2L/TRAIL stimulates cancer cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyltransferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non-small-cell lung carcinoma and melanoma cell lines, and up to 30% of samples from various human malignancies showed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-(N-acetyl galactosamine-galactose-sialic acid) structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptotic signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a new link between death-receptor O-glycosylation and apoptotic signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy.

Research paper thumbnail of Abstract 417: A novel predictive biomarker model for MEK sensitivity

Research paper thumbnail of 5002 ORAL Results from a Phase II randomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer

Research paper thumbnail of Extending survival of cancer patients with elevated levels of EGF or TGF-alpha

Research paper thumbnail of Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors

Research paper thumbnail of Predicting response to a HER inhibitor

Research paper thumbnail of Predicting response to a her dimerisation inhbitor based on low her3 expression

Research paper thumbnail of Predicting response to a HER inhibitor. Genentech, Hoffmann La Roche July 19, 2011

Research paper thumbnail of Human Homologue of a Candidate for the Mom1 Locus, the Secretory Type II Phospholipase A2 (PLA2S-II), Maps to 1p35-36.1/D1S199

Cancer Research, Dec 1, 1995

Research paper thumbnail of 414 Correlation of mutations in EGFR with clinical outcomes in NSCLC patients treated with erlotinib

European Journal of Cancer Supplements, 2004

Research paper thumbnail of Abstract 3500: Analysis of the prevalence and prognostic significance of 92 endpoints using high throughput multiplexed qPCR In archival tissue from multiple NSCLC trials

Research paper thumbnail of Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors

Clinical cancer research : an official journal of the American Association for Cancer Research, 2015

The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-d... more The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, f...

Research paper thumbnail of Abstract 3231: Comprehensive profiling of actionab

Research paper thumbnail of Up-Regulation of Periostin and Reactive Stroma is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 2, 2015

Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatmen... more Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation data set containing 138 ovarian patients from the chemo-treatment arm of ICON7 trial. We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in post-treatment recurrent tumors. IHC and RNA ISH analyses on three of the highest-ranked signature genes (POSTN, LOX and FAP) confirmed that modulation of the reactive stroma signature genes within the p...

Research paper thumbnail of Abstract 3527: Assessing signal modulation in preclinical models and tumor tissue from patients enrolled in a Phase 1 study of the HER3/EGFR dual action antibody, MEHD7945A (MEHD), as an exploratory pharmacodynamic (PD) analysis

Research paper thumbnail of Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer

Breast Cancer Research, 2014

Introduction: The purpose of this study was to retrospectively explore the relationship between h... more Introduction: The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1).

Research paper thumbnail of Identification and Characterization of Novel Genes Located at the t(1;15)(p36.2;q24) Translocation Breakpoint in the Neuroblastoma Cell Line NGP

Genomics, 2000

The distal portion of chromosome 1p is frequently deleted in several human cancers, suggesting th... more The distal portion of chromosome 1p is frequently deleted in several human cancers, suggesting the presence of one or more putative tumor suppressor genes on this chromosomal arm. In human neuroblastoma, a consistently deleted region at 1p36.1–p36.2 has been defined by comparison of molecular loss of heterozygosity (LOH) analyses. Recently we described the identification of a yeast artificial chromosome, YAC

Research paper thumbnail of TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer

Science Signaling, 2011

The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of t... more The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to-mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra-1), which is found in basal-like breast cancers but not in the luminal subtype, stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. Furthermore, miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting the 3' untranslated region of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1), which inhibited EMT by decreasing ZEB2 (zinc finger E-box-binding homeobox2) expression. We conclude that by promoting EMT, miR-221/222 may contribute to the more aggressive clinical behavior of basal-like breast cancers.

Research paper thumbnail of Secretory Type II Phospholipase A2 (PLA2G2A) expression status in colorectal carcinoma derived cell lines and in normal colonic mucosa

Oncogene, 1998

There is good evidence now that the secretory type II phospholipase A 2 (Pla2g2a) gene represents... more There is good evidence now that the secretory type II phospholipase A 2 (Pla2g2a) gene represents the Mom1 locus, a genetic modi®er of tumor resistance in the multiple intestinal neoplasia (Min) mouse. Previously we have mapped the human homolog PLA2G2A to 1p35-36.1 within a region that is the target of frequent deletions in sporadic colorectal tumors. Here we show 64% loss of heterozygosity (LOH) at the PLA2G2A locus in primary tumors. We studied PLA2G2A expression in both colorectal tumor cell lines and normal mucosa. Most of the lines lacked detectable PLA2G2A transcripts by Northern analysis. Large dierences in expression were seen among normal mucosa of dierent patients with sporadic tumors. We analysed the coding region of PLA2G2A in eight colorectal cancer cell lines with hemizygous deletion at 1p35-36/PLA2G2A, in none we did detect a mutation. Biallelic expression of PLA2G2A was observed in a cell line heterozygous for an exon 3 polymorphism, rendering unlikely that imprinting is a pathway participating in the loss of PLA2G2A function. It remains uncertain if PLA2G2A, in particular its apparent lack of expression in tumor cells, might be a factor in human colorectal tumorigenesis.

Research paper thumbnail of Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

Journal of Clinical Oncology, 2010

Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor recepto... more Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor receptor 2 (HER2) heterodimerization and has single-agent activity in recurrent epithelial ovarian cancer. The primary objective of this phase II study was to characterize the safety and estimate progression-free survival (PFS) of pertuzumab with gemcitabine in patients with platinum-resistant ovarian cancer. Patients with advanced, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received a maximum of one prior treatment for recurrent cancer were randomly assigned to gemcitabine plus either pertuzumab or placebo. Collection of archival tissue was mandatory to permit exploration of biomarkers that would predict benefit from pertuzumab in this setting. One hundred thirty patients (65 per arm) were treated. Baseline characteristics were similar between arms. The adjusted hazard ratio (HR) for PFS was 0.66 (95% CI, 0.43 to 1.03; P = .07) in favor of gemcitabine + pertuzumab. The objective response rate was 13.8% in patients who received gemcitabine + pertuzumab compared with 4.6% in patients who received gemcitabine + placebo. In patients whose tumors had low HER3 mRNA expression (< median, n = 61), an increased treatment benefit was observed in the gemcitabine + pertuzumab arm compared with the gemcitabine alone arm (PFS HR = 0.32; 95% CI, 0.17 to 0.59; P = .0002). Grade 3 to 4 neutropenia, diarrhea, and back pain were increased in patients treated with gemcitabine + pertuzumab. Symptomatic congestive heart failure was reported in one patient in the gemcitabine + pertuzumab arm. Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer. Low HER3 mRNA expression may predict pertuzumab clinical benefit and be a valuable prognostic marker.

Research paper thumbnail of Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Nature Medicine, 2007

Apo2L/TRAIL stimulates cancer cell death through the proapoptotic receptors DR4 and DR5, but the ... more Apo2L/TRAIL stimulates cancer cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyltransferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non-small-cell lung carcinoma and melanoma cell lines, and up to 30% of samples from various human malignancies showed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-(N-acetyl galactosamine-galactose-sialic acid) structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptotic signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a new link between death-receptor O-glycosylation and apoptotic signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy.

Research paper thumbnail of Abstract 417: A novel predictive biomarker model for MEK sensitivity

Research paper thumbnail of 5002 ORAL Results from a Phase II randomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer

Research paper thumbnail of Extending survival of cancer patients with elevated levels of EGF or TGF-alpha

Research paper thumbnail of Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors

Research paper thumbnail of Predicting response to a HER inhibitor

Research paper thumbnail of Predicting response to a her dimerisation inhbitor based on low her3 expression

Research paper thumbnail of Predicting response to a HER inhibitor. Genentech, Hoffmann La Roche July 19, 2011

Research paper thumbnail of Human Homologue of a Candidate for the Mom1 Locus, the Secretory Type II Phospholipase A2 (PLA2S-II), Maps to 1p35-36.1/D1S199

Cancer Research, Dec 1, 1995

Research paper thumbnail of 414 Correlation of mutations in EGFR with clinical outcomes in NSCLC patients treated with erlotinib

European Journal of Cancer Supplements, 2004

Research paper thumbnail of Abstract 3500: Analysis of the prevalence and prognostic significance of 92 endpoints using high throughput multiplexed qPCR In archival tissue from multiple NSCLC trials

Research paper thumbnail of Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors

Clinical cancer research : an official journal of the American Association for Cancer Research, 2015

The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-d... more The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, f...

Research paper thumbnail of Abstract 3231: Comprehensive profiling of actionab

Research paper thumbnail of Up-Regulation of Periostin and Reactive Stroma is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 2, 2015

Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatmen... more Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation data set containing 138 ovarian patients from the chemo-treatment arm of ICON7 trial. We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in post-treatment recurrent tumors. IHC and RNA ISH analyses on three of the highest-ranked signature genes (POSTN, LOX and FAP) confirmed that modulation of the reactive stroma signature genes within the p...

Research paper thumbnail of Abstract 3527: Assessing signal modulation in preclinical models and tumor tissue from patients enrolled in a Phase 1 study of the HER3/EGFR dual action antibody, MEHD7945A (MEHD), as an exploratory pharmacodynamic (PD) analysis

Research paper thumbnail of Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer

Breast Cancer Research, 2014

Introduction: The purpose of this study was to retrospectively explore the relationship between h... more Introduction: The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1).

Research paper thumbnail of Identification and Characterization of Novel Genes Located at the t(1;15)(p36.2;q24) Translocation Breakpoint in the Neuroblastoma Cell Line NGP

Genomics, 2000

The distal portion of chromosome 1p is frequently deleted in several human cancers, suggesting th... more The distal portion of chromosome 1p is frequently deleted in several human cancers, suggesting the presence of one or more putative tumor suppressor genes on this chromosomal arm. In human neuroblastoma, a consistently deleted region at 1p36.1–p36.2 has been defined by comparison of molecular loss of heterozygosity (LOH) analyses. Recently we described the identification of a yeast artificial chromosome, YAC

Research paper thumbnail of TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer

Science Signaling, 2011

The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of t... more The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to-mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra-1), which is found in basal-like breast cancers but not in the luminal subtype, stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. Furthermore, miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting the 3' untranslated region of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1), which inhibited EMT by decreasing ZEB2 (zinc finger E-box-binding homeobox2) expression. We conclude that by promoting EMT, miR-221/222 may contribute to the more aggressive clinical behavior of basal-like breast cancers.

Research paper thumbnail of Secretory Type II Phospholipase A2 (PLA2G2A) expression status in colorectal carcinoma derived cell lines and in normal colonic mucosa

Oncogene, 1998

There is good evidence now that the secretory type II phospholipase A 2 (Pla2g2a) gene represents... more There is good evidence now that the secretory type II phospholipase A 2 (Pla2g2a) gene represents the Mom1 locus, a genetic modi®er of tumor resistance in the multiple intestinal neoplasia (Min) mouse. Previously we have mapped the human homolog PLA2G2A to 1p35-36.1 within a region that is the target of frequent deletions in sporadic colorectal tumors. Here we show 64% loss of heterozygosity (LOH) at the PLA2G2A locus in primary tumors. We studied PLA2G2A expression in both colorectal tumor cell lines and normal mucosa. Most of the lines lacked detectable PLA2G2A transcripts by Northern analysis. Large dierences in expression were seen among normal mucosa of dierent patients with sporadic tumors. We analysed the coding region of PLA2G2A in eight colorectal cancer cell lines with hemizygous deletion at 1p35-36/PLA2G2A, in none we did detect a mutation. Biallelic expression of PLA2G2A was observed in a cell line heterozygous for an exon 3 polymorphism, rendering unlikely that imprinting is a pathway participating in the loss of PLA2G2A function. It remains uncertain if PLA2G2A, in particular its apparent lack of expression in tumor cells, might be a factor in human colorectal tumorigenesis.

Research paper thumbnail of Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

Journal of Clinical Oncology, 2010

Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor recepto... more Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor receptor 2 (HER2) heterodimerization and has single-agent activity in recurrent epithelial ovarian cancer. The primary objective of this phase II study was to characterize the safety and estimate progression-free survival (PFS) of pertuzumab with gemcitabine in patients with platinum-resistant ovarian cancer. Patients with advanced, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received a maximum of one prior treatment for recurrent cancer were randomly assigned to gemcitabine plus either pertuzumab or placebo. Collection of archival tissue was mandatory to permit exploration of biomarkers that would predict benefit from pertuzumab in this setting. One hundred thirty patients (65 per arm) were treated. Baseline characteristics were similar between arms. The adjusted hazard ratio (HR) for PFS was 0.66 (95% CI, 0.43 to 1.03; P = .07) in favor of gemcitabine + pertuzumab. The objective response rate was 13.8% in patients who received gemcitabine + pertuzumab compared with 4.6% in patients who received gemcitabine + placebo. In patients whose tumors had low HER3 mRNA expression (< median, n = 61), an increased treatment benefit was observed in the gemcitabine + pertuzumab arm compared with the gemcitabine alone arm (PFS HR = 0.32; 95% CI, 0.17 to 0.59; P = .0002). Grade 3 to 4 neutropenia, diarrhea, and back pain were increased in patients treated with gemcitabine + pertuzumab. Symptomatic congestive heart failure was reported in one patient in the gemcitabine + pertuzumab arm. Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer. Low HER3 mRNA expression may predict pertuzumab clinical benefit and be a valuable prognostic marker.