scholarly journals OS5.3 Quantitative signaling pathway analysis of Diffuse Intrinsic Pontine Glioma identifies two subtypes, respectively high TGFβ/MAPK-AP1 and high PI3K/HH pathway activity, which are potentially clinically actionable

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii11-iii11
Author(s):  
A van de Stolpe ◽  
W Verhaegh ◽  
L Holtzer
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Pi3k Pathway ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade Glioma ◽  
Signal Transduction Pathways ◽  
Low Grade ◽  
Pontine Glioma ◽  
Pathway Activity

Abstract BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric brain tumor (glioma), resistant to chemotherapy, with only a temporary response to radiotherapy and an extremely bad prognosis. Genomic abnormalities have been found, indicating abnormal activation of certain growth factor signaling pathways, while expression analysis suggests involvement of developmental signaling pathways.10–15 signal transduction pathways can drive cancer growth and metastasis. We have developed, and biologically validated, a method which enables quantitative measurements of functional activity of signal transduction pathways in individual cell/tissue samples, based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the transcription factor associated with the respective signalling pathway. A major envisioned clinical utility is prediction of therapy response. MATERIAL AND METHODS For signaling pathway analysis, Affymetrix expression microarray data were available (GEO dataset GSE26576) from 2 normal brain stem samples and from 6 low grade glioma and 26 DIPG samples (post-mortem after therapy). Of one DIPG patient samples were available before and after therapy. Signaling pathway activity scores were calculated for estrogen and androgen receptor, PI3K-FOXO, MAPK-AP1, JAK-STAT, NFκB, Hedgehog (HH), TGFβ, NOTCH and Wnt pathways. PI3K pathway activity is the reverse of FOXO activity, in the absence of oxidative stress (measured by SOD2 expression). Pathway activity scores were compared between normal tissue and low grade glioma samples and DIPG, and k-means cluster analysis was performed on the DIPG pathway activity scores. RESULTS After treatment, HH pathway activity was increased in DIPG compared to low grade glioma (p=0.0003), PI3K pathway activity scores showed large variations in activity in the DIPG group. Tumors with cell cycle (CDK4/6, CCND1-3) or Receptor Tyrosine Kinase-related gene amplifications had higher PI3K and HH pathway activity compared to tumors without identified amplifications (p<0.05) which, in contrast, had higher MAPK-AP1 pathway activity (p<0.002). Pathway-based clustering analysis revealed two DIPG clusters, C1: high TGFβ/MAPK-AP1 and low PI3K/HH pathway activity; C2: low TGFβ/MAPK-AP1, high PI3K/HH pathway activity. C1 best resembled low grade glioma. In the patient with pre/post treatment samples, a C1 pathway profile switched to a C2 profile after treatment. CONCLUSION Using our quantitative analysis of signaling pathway activity in post-treatment DIPG, two pathway activity subtypes were identified, of which the HH/PI3K high, TGFβ low activity subtype was associated with defined gene amplifications, and may have been induced by chemoradiation therapy. Clusters are supported by a clear biological rationale. Identified signaling pathways are potentially drug targetable.

scholarly journals Quantitative Measurement of Functional Activity of the PI3K Signaling Pathway in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 293 ◽  
Author(s):  
Anja van de Stolpe
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Mtor Inhibitors ◽  
Therapy Resistance ◽  
Pi3k Pathway ◽  
Growth Factor Signaling ◽  
Mrna Levels ◽  
Tissue Samples ◽  
Pathway Activity ◽  
Phosphoinositide 3 Kinase

The phosphoinositide 3-kinase (PI3K) growth factor signaling pathway plays an important role in embryonic development and in many physiological processes, for example the generation of an immune response. The pathway is frequently activated in cancer, driving cell division and influencing the activity of other signaling pathways, such as the MAPK, JAK-STAT and TGFβ pathways, to enhance tumor growth, metastasis, and therapy resistance. Drugs that inhibit the pathway at various locations, e.g., receptor tyrosine kinase (RTK), PI3K, AKT and mTOR inhibitors, are clinically available. To predict drug response versus resistance, tests that measure PI3K pathway activity in a patient sample, preferably in combination with measuring the activity of other signaling pathways to identify potential resistance pathways, are needed. However, tests for signaling pathway activity are lacking, hampering optimal clinical application of these drugs. We recently reported the development and biological validation of a test that provides a quantitative PI3K pathway activity score for individual cell and tissue samples across cancer types, based on measuring Forkhead Box O (FOXO) transcription factor target gene mRNA levels in combination with a Bayesian computational interpretation model. A similar approach has been used to develop tests for other signaling pathways (e.g., estrogen and androgen receptor, Hedgehog, TGFβ, Wnt and NFκB pathways). The potential utility of the test is discussed, e.g., to predict response and resistance to targeted drugs, immunotherapy, radiation and chemotherapy, as well as (pre-) clinical research and drug development.

scholarly journals DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii294-iii295
Author(s):  
Jovana Pavisic ◽  
Chankrit Sethi ◽  
Chris Jones ◽  
Stergios Zacharoulis ◽  
Andrea Califano
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade ◽  
Precision Oncology ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Master Regulator

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of &gt;100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

scholarly journals PEDT-02 DIAGNOSIS, TREATMENT AND CLINICAL OUTCOME OF ATYPICAL BRAINSTEM TUMOUR IN CHILDHOOD

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii16-ii16
Author(s):  
Takaaki Yanagisawa ◽  
Takaya Honda ◽  
Masatada Yamaoka ◽  
Masaharu Akiyama ◽  
Kohei Fukuoka ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Survival Data ◽  
Treatment Strategy ◽  
Retrospective Chart Review ◽  
Malignant Tumour ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Clinical Findings ◽  
Low Grade Glioma ◽  
Pathological Diagnosis ◽  
Low Grade

Abstract BACKGROUND Brainstem tumours account for 10–15% of brain tumors in childhood. Diffuse intrinsic pontine glioma (DIPG) accounts for 60–80% of them and are diagnosed based on clinical findings and radiologic features. All the rest of tumours excluding DIPG are very rare, heterogeneous group of tumours including low-grade glioma and malignant embryonal tumors. It is often difficult to diagnose and decide treatment strategy for their rarity. METHODS To present our experience with atypical brainstem tumours, a retrospective chart review was conducted to identify eligible cases treated over a ten-year period. All tumors involving brainstem, felt not to be DIPGs for absence of clinical/neuroimaging features were included. Demographic information, pathological findings, neuroimaging characteristics, surgical and nonsurgical management plans, and survival data were collected for analysis. RESULTS Between April 2007 and March 2017, 16 patients (14 initial and 2 recurrent) aged from 3 to 20 years were identified. 14 of them were symptomatic and 4 of them were asymptomatic at reference. Of 10 symptomatic cases, 10 were biopsied and pathological diagnosis was low-grade glioma in 8, glioblastoma in 2 cases. They had treatment depending on the pathological diagnosis. Of 4 asymptomatic cases, one with small focal tumour, with no findings suggesting malignant tumour with 11C-methioninePET or MRS, progressed to show typical clinical and image findings of DIPG in a year. For other three, they remain asymptomatic without progression with no treatment for 25months, 60months, and 65 months respectively. Malignant transformation was observed in one with biopsy-conformed oligoastrocytoma with no K27M-H3 mutations treated with chemotherapy and another with pilocytic astrocytoma treated with chemotherapy and radiotherapy. CONCLUSIONS Though molecular findings such as K27M-H3 mutations can predict clinical outcome in some cases, it still remains difficult to diagnose and find treatment strategy of atypical brainstem tumours. The need and usefulness of nationwide registry study is warranted.

Identification of Novel Biologic Targets in the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Glioma

2012 ◽  
pp. 625-628
Author(s):  
Nathan J. Robison ◽  
Mark W. Kieran
Keyword(s):  
Pi3k Pathway ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Experimental Therapy ◽  
Murine Models ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Molecular Features ◽  
Autopsy Series ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
P53 Inactivation

Overview: Diffuse intrinsic pontine gliomas (DIPGs) carry an extremely poor prognosis. Standard practice has been to base the diagnosis on classic imaging and clinical characteristics and to treat with focal radiation therapy, usually accompanied with experimental therapy. As a result of the desire to avoid upfront biopsy, little has been learned regarding the molecular features of this disease. Findings from several autopsy series have included loss of p53 and PTEN, and amplification of PDGFR. Based on these and other findings, murine models have been generated and provide a new tool for preclinical testing. DIPG biopsy at diagnosis has increasingly become incorporated into national protocols at several centers, bringing the prospect of a better understanding of DIPG biology in the future. Initial analyses of pretreatment tumors cast valuable new light and establish the importance of p53 inactivation and the RTK-PI3K pathway in this disease.

scholarly journals Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low-grade glioma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiajie Lu ◽  
Yuecheng Peng ◽  
Rihong Huang ◽  
Zejia Feng ◽  
Yongyang Fan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Signaling Pathway ◽  
Low Grade Glioma ◽  
Gene Set Enrichment Analysis ◽  
Low Grade ◽  
Ppi Network ◽  
Myeloid Dendritic Cells ◽  
Immune Infiltration ◽  
Normal Tissues ◽  
Worse Prognosis

Abstract Background Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). Methods The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

scholarly journals Integrative Bioinformatics and Experimental Investigation Introduces OBI1-AS1 as a Key LncRNA in the Progression of Low-grade Glioma to Glioblastoma

2021 ◽  
Author(s):  
Ali Mamivand ◽  
Shiva Bayat ◽  
Abolfazl Maghrouni ◽  
Sasan Shabani ◽  
Alireza Khoshnevisan ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Experimental Investigation ◽  
Neural Differentiation ◽  
Bioinformatics Analysis ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Multiple Functions ◽  
Histological Features ◽  
Therapeutic Measures ◽  
Non Coding Rnas

Abstract Background:Long non-coding RNAs (LncRNAs) are widely known for their multiple functions in the context of cancer from tumor initiation to tumor progression and metastasis. Gliomas are the most prevalent primary forms of brain tumor, classed from grades I to IV according to their malignant histological features with grade IV also known as Glioblastoma Multiforme (GBM) displaying the highest level of malignancy. This fact intensifies the importance of searching for Differentially Expressed LncRNAs (DELncRNAs) between GBM and Low-Grade Glioma in the hope of finding new targets for diagnostic and therapeutic measures. Methods: In the current study, we performed bioinformatics analysis to obtain a list of DELncRNAs and further chose the unprecedentedly studied OBI1-AS1 for further investigations. We also carried out Real-Time PCR to validate our bioinformatics findings.Results:Both analyses were in concordance and pinpointed downregulated expression of OBI1-AS1 in GBM compared to LGG samples. Additional supplementary bioinformatics studies exhibited OBI1-AS1 role in synaptic signal transduction and neural differentiation in addition to its role in pluripotency and maintenance of stemness. Conclusion:All the aforementioned findings introduce OBI1-AS1 as a new attractive lncRNA to be further studied for a better clarification of its roles in glioma progression and a deeper understanding of malignant transformation of LGG to GBM.

scholarly journals Predicting mechanism of action of cellular perturbations with pathway activity signatures

2019 ◽  
Author(s):  
Yan Ren ◽  
Siva Sivaganesan ◽  
Nicholas A. Clark ◽  
Lixia Zhang ◽  
Jacek Biesiada ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Mechanism Of Action ◽  
Therapeutic Potential ◽  
R Package ◽  
Difficult Problem ◽  
Computational Method ◽  
Integrated Analysis ◽  
Pathway Activity ◽  
Transcriptional Signature

ABSTRACTMotivationMisregulation of signaling pathway activity is etiologic for many human diseases, and modulating activity of signaling pathways is often the preferred therapeutic strategy. Understanding the mechanism of action (MOA) of bioactive chemicals in terms of targeted signaling pathways is the essential first step in evaluating their therapeutic potential. Changes in signaling pathway activity are often not reflected in changes in expression of pathway genes which makes MOA inferences from transcriptional signatures a difficult problem.ResultsWe developed a new computational method for implicating pathway targets of bioactive chemicals and other cellular perturbations by integrated analysis of pathway network topology, the LINCS transcriptional signatures of genetic perturbations of pathway genes and the transcriptional signature of the perturbation. Our methodology accurately predicts signaling pathways targeted by the perturbation when current pathway analysis approaches utilizing only a transcriptional signature of the perturbation fail.Availability and ImplementationOpen source R package paslincs is available at https://github.com/uc-bd2k/paslincs.

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