Birgit Schoeberl

Birgit Schoeberl
Novartis Institutes for BioMedical Research | NIBR · Translational Medicine

About

112
Publications
9,642
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
4,239
Citations
Introduction
Skills and Expertise

Publications

Publications (112)
Article
Full-text available
Therapeutically targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes. Insulin-Like Growth Factor Receptor 1 (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) have been implicated as two such drivers of resistance, however their simultaneo...
Article
Recent advances in experimentation and computation have allowed us to build multiscale models of unprecedented scale. Quantitative Systems Pharmacology (QSP) models are multiscale models that link protein-interaction or drug-interaction kinetics to cellular response in the context of animal or human (disease) physiology. One of the areas where QSP...
Conference Paper
In colorectal cancer (CRC), RAS mutated cancers comprise 30-50%, for which there are limited treatment options. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been found to selectively induce cell death in 50% of the CRC cell lines tested and this appears to be independent of RAS mutation status. Minimal clinical success...
Conference Paper
In colorectal cancer (CRC), RAS mutated cancers comprise 30-50%, for which there are limited treatment options. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been found to selectively induce cell death in 50% of the CRC cell lines tested and this appears to be independent of RAS mutation status. Minimal clinical success...
Article
Full-text available
Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challeng...
Article
Full-text available
We introduce a tensor-based clustering method to extract sparse, low-dimensional structure from high-dimensional, multi-indexed datasets. This framework is designed to enable detection of clusters of data in the presence of structural requirements which we encode as algebraic constraints in a linear program. Our clustering method is general and can...
Data
Supplementary Information for: Tensor clustering with algebraic constraints gives interpretable groups of crosstalk mechanisms in breast cancer
Article
Full-text available
Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multiscale computational model that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate. The computational model was trained and calib...
Conference Paper
Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multi-scale computational model using the U2OS osteosarcoma cancer cell line that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate....
Conference Paper
Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors for growth factors that are frequently deregulated in cancer. Signaling through these receptors has been associated with increased cancer cell proliferation and resistance to cytotoxic therapies. To block this detrimental signaling, many companies are developing inhibitory an...
Article
Full-text available
Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to un...
Article
Full-text available
Targeted therapies have shown significant patient benefit in about 5–10% of solid tumors that are addicted to a single oncogene. Here, we explore the idea of ligand addiction as a driver of tumor growth. High ligand levels in tumors have been shown to be associated with impaired patient survival, but targeted therapies have not yet shown great bene...
Article
Full-text available
As interactions between the immune system and tumour cells are governed by a complex network of cell-cell interactions, knowing the specific immune cell composition of a solid tumour may be essential to predict a patient's response to immunotherapy. Here, we analyse in depth how to derive the cellular composition of a solid tumour from bulk gene ex...
Article
Full-text available
Aberrant signaling of the FGFR pathway has long been known to promote tumorigenesis and angiogenesis across multiple cancer indications. However, the development of an effective and well-tolerated FGFR targeted inhibitor has been hindered by the need to block the activation of multiple mitogenic receptors while avoiding significant toxicities assoc...
Conference Paper
Although therapeutics that modulate the immune system provide remarkable benefit for many cancer patients, predicting who will respond remains an unsolved problem. As interactions between the immune system and cancer are governed by a complex network of cell-cell interactions, knowing the specific immune cell composition of a solid tumour may be es...
Article
Within wild-type colorectal cancer (-wt CRC), standard of care treatment includes EGFR-directed monoclonal antibodies (mAb) in combination with an irinotecan-based chemotherapy regimen. While such combinations have clinically established synergy, the underlying mechanisms of synergy remain elusive, and resistance invariably develops against either...
Article
Ewing’s sarcoma family tumors (ES) are aggressive tumors that often present as metastatic in bone and soft tissue and predominantly affect adolescents and younger adults. Current treatment for ES includes surgical resection followed by loco-regional radiotherapy and chemotherapy. Survival rates for patients with metastatic disease continue to offer...
Preprint
Targeted therapies have shown significant patient benefit in about 5-10% of solid tumors that are addicted to a single oncogene. Here, we explore the idea of ligand addiction as a driver of tumor growth. High ligand levels in tumors have been shown to be associated with impaired patient survival, but targeted therapies have not yet shown great bene...
Preprint
As interactions between the immune system and tumour cells are governed by a complex network of cell-cell interactions, knowing the specific immune cell composition of a solid tumour may be essential to predict a patient’s response to immunotherapy. Here, we analyse in depth how to derive the cellular composition of a solid tumour from bulk gene ex...
Article
Full-text available
The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1), human EGFR 2 (HER2/ErbB2), ErbB3/HER3, and ErbB4/HER4. The first two members of this family, EGFR and HER2, have been implicated in tumorigenesis and cancer progression for several decades, and numerous drugs have now been approved th...
Article
Full-text available
We introduce a tensor-based algebraic clustering method to extract sparse, low-dimensional structure from multidimensional arrays of experimental data. Our methodology is applicable to high dimensional data structures that arise across the sciences. Specifically we introduce a new way to cluster data subject to multi-indexed structural constraints...
Article
Taxanes are widely used to treat solid tumors either in the curative or palliative setting, in first or later lines of therapy. Analysis of docetaxel dose-response relationship strongly suggests that a higher dose would lead to high response, however will also lead to higher toxicity. This is likely related to the lack of organ and cellular specifi...
Conference Paper
Protein-based agonists of apoptotic death receptors have shown remarkable preclinical efficacy but limited clinical response. The short circulating half-life of recombinant human TRAIL and the necessity of Fc-mediated clustering for potentiating agonistic antibodies against DR4 and DR5 have been proposed to be major impediments to the clinical succ...
Article
Full-text available
Understanding the molecular pathways by which oncogenes drive cancerous cell growth, and how dependence on such pathways varies between tumors could be highly valuable for the design of anti-cancer treatment strategies. In this work we study how dependence upon the canonical PI3K and MAPK cascades varies across HER2+ cancers, and define biomarkers...
Data
Quantitative logic-based models of cell growth regulation by ERK and AKT signals. (A) Generic logic model; combinations of OR, AND, or null (K) gates can be combined to describe signal-response relationships. (B) Quantitative comparison of 9 alternate model forms across all cell lines, based on Akaike Information Criterion (AIC) minimization. (C) W...
Data
Select model parameter estimates and precision for each cell line +/- heregulin (HRG) stimulation. AKT and ERK weights for each cell line +/- HRG are shown in (A, B). (C) Median coefficient of variation (CV) +/- 1 standard deviation across the cell line panel for each of the four model parameters, the relations (Pathway Bais, and umax/dmax) as well...
Data
Multivariate logistic model-based classification of Pathway Bias. Comparison of logistic model accuracy built using alternate sets of input features. Predictions from alternate models were evaluated via Pearson correlation coefficients, Mean Squared Error (MSE), and accuracy as compared to randomized data. (PPTX)
Data
Cell surface response plots of cell population doubling (PD) 96-hour following treatment with AKT (MK2206) and MEK (GSK1120212) inhibitor matrices. Cell surface responses from ZR75-1 and ZR75-30 are depicted in individual boxes. Top panels show data from FBS-supplemented media, and bottom panels with 2nM heregulin ligand (HRG) addition. Left plots...
Data
Expression of ERBB3, EGFR, and CDKN1B across multiple HER2+ cancer indications represented in TCGA. (A) Raw RNAseq counts are displayed for all indications, and HER2+ defined as samples with greater than 15,000 counts. (B) Differential expression for each gene compared to breast cancers, separated by HER2+ and HER2- populations. (PPTX)
Data
Spearman’s Rank Correlation coefficients between sensitivities to select pathway inhibitors across all cell lines in the GDSC database. Asterisks indicate drugs identified as differentially sensitive between predicted PI3K (blue) and MAPK (red) cell subsets. (PPTX)
Data
Basal protein expression (column normalized) for the 18 cell lines +/- heregulin (HRG). Data is represented using a hierarchical clustered heatmap, and PI3K, MAPK, and SWITCH classification scheme color-coded for each cell. (PPTX)
Data
“M4” Model Parameters and associated error. (DOCX)
Data
Excel spreadsheet containing mean cell growth response data, Luminex protein signals, logic model parameter estimates and simulations. (XLSX)
Data
Cell surface response plots of cell population doubling (PD) 96-hour following treatment with AKT (MK2206) and MEK (GSK1120212) inhibitor matrices. Cell surface responses from AU565, BT474-M3, CALU3, HCC202, HCC1419, HCC1954, JIMT1 and MDAMB175VII are depicted in individual boxes. Top panels show data from FBS-supplemented media, and bottom panels...
Data
Cell surface response plots of cell population doubling (PD) 96-hour following treatment with AKT (MK2206) and MEK (GSK1120212) inhibitor matrices. Cell surface responses from MDAMB361, MDAMB453, NCI-N87, NCI-H2170, OE19, OE33, SKBR3 and SKOV3 are depicted in individual boxes. Top panels show data from FBS-supplemented media, and bottom panels with...
Data
Heregulin-induced changes in protein expression across cell lines. Data is represented as z-scores (heregulin-stimulated vs. FBS), and cell lines classified into PI3K, MAPK, and SWITCH categories (PPTX)
Data
Rank correlation coefficients between expressions of protein and mRNA (A) and mRNA-mRNA (B). mRNA expression is taken from the CCLE database (RMA values), and protein expression from two sources; our 18-cell line Luminex profile (18 HER2+) and an internal ELISA-based profile (MBASE) segregated into HER2+ and all cells. (PPTX)
Data
Summary of logic-based cell growth models evaluated. (DOCX)
Data
Statistics associated with EGFR, ERBB3, and CDKN1B mRNA expression, and PIK3CA mutation-based stratification of shRNA knockdown data from Project Achilles. (XLSX)
Data
A) Capture antibodies used in Luminex assays. B) Detection antibodies used in Luminex assays. (DOCX)
Data
Logistic model parameters, wherein median values and standard deviations are taken from the 36 LOOCV estimates. (DOCX)
Data
Raw Protein Signals, and Logistic Model Predictions of Pathway Bias. (DOCX)
Data
Evaluation of EGFR, ERBB3, pAKT, and pERK protein expression as predictive biomarkers for HDACi, PI3K/AKT/MTORi, and MEKi sensitivity in HER2+ cell represented in the GDSC Database. (DOCX)
Chapter
ErbB3/HER3 belongs to the family of ErbB receptors, which comprises four transmembrane receptors that can bind more than ten different ligands. The ErbB3 receptor forms heterodimers with the other ErbB receptor family members, which is the necessary step to activate downstream prosurvival signaling. While ErbB3 signaling plays an important role in...
Article
In this weeks issue of Science Signaling, Fey et al. introduce a new type of biomarker. Using the example of neuroblastoma, the authors demonstrate that patientspecifi c differences in the computed property (the Hill coeffi cient) of the dynamics of a pathway involved in cell death signaling outperformed the prognostic capability of any single stat...
Conference Paper
The trimeric TNF-related apoptosis-inducing ligand (TRAIL) is an endogenous ligand that binds to trimeric death receptors (DR4/5). TRAIL is known to induce apoptosis mainly in malignant cells while normal cells remain unaffected. This makes TRAIL a most interesting target for cancer therapy. We investigate the effects of ligand valency on the degre...
Conference Paper
s: AACR Special Conference: Computational and Systems Biology of Cancer; February 8-11, 2015; San Francisco, CA Most commonly used anti-cancer therapies involve the systemic administration of anti-proliferative and DNA damaging agents. Deregulation of DNA damage response (DDR) pathways can cause resistance to DNA damaging therapies. Synergistic co...
Article
Purpose: MM-131 is a purely antagonistic, bispecific antibody that potently inhibits HGF/c-Met signaling by co-targeting the widely expressed tumor antigen EpCAM. The purpose of these studies is to uncover the mechanism by which MM-131 exhibits potent inhibition of both HGF-dependent and HGF-independent c-Met signaling in EpCAM positive tumor cells...
Conference Paper
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Purpose: Heregulin-mediated activation of the human epidermal growth factor receptor 3 (HER3/ErbB3) is required for the growth and survival of many epithelial cancers. This signaling pathway is also emerging as a mechanism of resistance to targeted agents and chemothe...
Article
Full-text available
Modeling of dynamical systems using ordinary differential equations is a popular approach in the field of Systems Biology. Two of the most critical steps in this approach are to construct dynamical models of biochemical reaction networks for large data sets and complex experimental conditions and to perform efficient and reliable parameter estimati...
Article
Interleukin-1 is one of the inflammatory cytokines elevated after traumatic joint injury that plays a critical role in mediating cartilage tissue degradation, suppressing matrix biosynthesis, and inducing chondrocyte apoptosis, events associated with progression to post-traumatic osteoarthritis (PTOA). We studied the combined use of insulin-like gr...
Article
Full-text available
Osteoclasts are responsible for bone destruction in degenerative, inflammatory and metastatic bone disorders. Although osteoclastogenesis has been well-characterized in mouse models, many questions remain regarding the regulation of osteoclast formation in human diseases. We examined the regulation of human precursors induced to differentiate and f...
Article
Full-text available
Background The Fibroblast Growth Factor (FGF) pathway is driving various aspects of cellular responses in both normal and malignant cells. One interesting characteristic of this pathway is the biphasic nature of the cellular response to some FGF ligands like FGF2. Specifically, it has been shown that phenotypic behaviors controlled by FGF signaling...
Article
Purpose: Overall 5-year survival rates for patients diagnosed with pancreatic cancer is approximately 5.5% and most patients do not show durable responses to therapy. While monoclonal antibodies have significantly advanced our ability to treat cancer, their potential in pancreatic cancer is yet to be realized. We believe that targeted therapeutic s...
Article
Molecular subtype is a critical determinant of therapeutic approaches in breast cancer. The subtype is based on the expression of three receptors: The Her2/ErbB2 receptor tyrosine kinase (RTK), whose over-expression defines the HER2amp subtype, and the estrogen or progesterone nuclear hormone receptors, whose over-expression defines the HR+ subtype...
Article
Full-text available
Background: Soluble growth factors present in the microenvironment play a major role in tumor development, invasion, metastasis, and responsiveness to targeted therapies. While the biochemistry of growth factor-dependent signal transduction has been studied extensively in individual cell types, relatively little systematic data are available acros...
Article
Full-text available
Although inhibition of the IGF signaling pathway was expected to eliminate a key resistance mechanism for EGFR-driven cancers, the effectiveness of IGF-1R inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells both IGF-1R and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 h...
Article
Full-text available
Identifying factors responsible for variation in drug response is essential for the effective use of targeted therapeutics. We profiled signaling pathway activity in a collection of breast cancer cell lines before and after stimulation with physiologically relevant ligands, which revealed the variability in network activity among cells of known gen...
Article
Currently, clinicians use the levels of the hormone receptors for estrogen (ER) and progesterone (PR) and amplifications of the ErbB2 receptor tyrosine kinase (RTK) to distinguish three groups of breast cancers and guide the choice of therapeutic treatments. In this work we show that a limited number of measurements characterizing breast cancer cel...
Article
Identification of druggable targets along with new therapies in metastatic melanoma is a main concern given the bad prognosis of this disease in the metastatic setting. The development of targeted therapies for cancer has fundamentally changed the ways in which we develop new drugs, select therapy for patients, design and conduct clinical trials an...
Article
Full-text available
Many interesting studies aimed at elucidating the connectivity structure of biomolecular pathways make use of abundance measurements, and employ statistical and information theoretic approaches to assess connectivities. These studies often do not address the effects of the dynamics of the underlying biological system, yet dynamics give rise to impa...