Transcriptional Analysis of JAK/STAT Signaling in Glioblastoma Multiforme

Jain, Rekha; Dasgupta, Asmita; Moiyadi, Aliasgar; Srivastava, Sanjeeva

doi:10.2174/1875692111201010054

Cited by 6 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It also has an important role in regulating differentiation of normal neural stem cells and thus has an essential role in the development of the nervous system [ 35 ]. JAK2/STAT3 signaling becomes deregulated in most cancers and is over activated in BTICs and GBM [ 9 , 10 ]. Despite our improved understanding of the important role JAK2/STAT3 signaling plays in GBM pathogenesis, JAK2/STAT3 inhibitors have yet to be successfully translated to the clinic.…”

Section: Discussionmentioning

confidence: 99%

The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model

et al. 2017

View full text Add to dashboard Cite

PurposeThe prognosis for patients diagnosed with glioblastoma multiforme (GBM) remains dismal, with current treatment prolonging survival only modestly. As such, there remains a strong need for novel therapeutic strategies. The janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 pathway regulates many cellular processes in GBM, including survival, proliferation, invasion, anti-apoptosis, and immune evasion. Here, we evaluated the preclinical efficacy of pacritinib, a novel compound targeting JAK2, using a collection of diverse patient-derived brain tumor initiating cells (BTICs).Experimental designThe effects of pacritinib on BTIC viability and sphere forming capacity were evaluated in vitro using the alamarBlue and neurosphere assays, respectively. On-target inhibition of JAK2/STAT3 signaling was investigated using western blotting. The efficacy of pacritinib was tested in vivo in pharmacokinetic analyses, liver microsome analyses, and Kaplan-Meier survival studies.ResultsIn vitro, pacritinib decreased BTIC viability and sphere forming potential at low micromolar doses and demonstrated on-target inhibition of STAT3 signaling. Additionally, pacritinib was found to improve the response to temozolomide (TMZ) in TMZ-resistant BTICs. In vivo, systemic treatment with pacritinib demonstrated blood-brain barrier penetration and led to improved overall median survival in combination with TMZ, in mice orthotopically xenografted with an aggressive recurrent GBM BTIC culture.ConclusionThis preclinical study demonstrates the efficacy of pacritinib and supports the feasibility of testing pacritinib for the treatment of GBM, in combination with the standard of care TMZ.

show abstract

Section: Discussionmentioning

confidence: 99%

The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Non-receptor tyrosine kinases that directly phosphorylate STATs are cytoplasmic kinases such as c-Src and Abl. The constitutive activation of JAK/STAT pathway and over-expression of STAT has been seen in many types of cancer including breast (Borgés et al, 2008;Hernandez-Vargas et al, 2011), prostate (Tam et al, 2007;Kroon et al, 2013), pancreatic (Denley, 2008), colorectal (Spano et al, 2006;Slattery et al, 2013), and brain (Jain et al, 2012). Therefore, STATs play critical roles in cancer progression, and they are being focused as potential target in cancer therapies.…”

Section: Jak/stat Signaling Pathway In Oncogenesismentioning

confidence: 99%

A Review: Phytochemicals Targeting JAK/STAT Signaling and IDO Expression in Cancer

Arumuggam

Bhowmick

Rupasinghe

2015

Phytotherapy Research

View full text Add to dashboard Cite

Cancer remains a major health problem worldwide. Among many other factors, two regulatory defects that are present in most cancer cells are constitutive activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and the induction of indoleamine 2, 3-dioxygenase (IDO), an enzyme that catalyzes tryptophan degradation, through JAK/STAT signaling. Cytokine signaling activates STAT proteins in regulating cell proliferation, differentiation, and survival through modulation of target genes. Many phytochemicals can inhibit both JAK/STAT signaling and IDO expression in antigen-presenting cells by targeting different pathways. Some of the promising phytochemicals that are discussed in this review include resveratrol, cucurbitacin, curcumin, (-)-epigallocatechin gallate, and others. It is now evident that phytochemicals play key roles in inhibition of tumor proliferation and development and provide novel means for therapeutic targeting of cancer.

show abstract

“…Although several molecular biomarkers have been identified, such as TP53 mutation and overexpression in EGFR (Bralten and French, 2011; Zhang et al, 2018), targeted therapy shows a limited effect (Shergalis et al, 2018; Banerjee et al, 2021). Recently, interest has focused on the molecular mechanism of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway (Jain et al, 2012; Ou et al, 2021). Here, the BMRF model is applied to the JAK-STAT signaling pathway to examine the conditional dependence among gene nodes and detect influential molecular relationships to understand the underlying biological mechanism better.…”

Section: The Glioblastoma Studymentioning

confidence: 99%

“…Liu and colleagues (Liu et al, 2011) have suggested PTPN11 as a functional target for treating glioblastomas in human and animal studies, and Cerami et al (2010) have identified PTPN11 as associated with an oncogenic process in GBM patients. Members of the PTPN family induce dephosphorylation of JAK , thereby regulating JAK-STAT signaling (Xu and Qu, 2008; Jain et al, 2012; Hammarén et al, 2019) In addition, the largest partial correlation was found between IRF9 and STAT1 . Au-Yeung et al (2013) noted that this interaction is involved in type I interferon (IFN) signaling and anti-viral immune response.…”

Section: The Glioblastoma Studymentioning

confidence: 99%

Probabilistic Edge Inference of Gene Networks with Bayesian Markov Random Field Modelling

Huang

Mukherjee

Hsiao

2022

Preprint

View full text Add to dashboard Cite

Gaussian graphical models (GGMs), also known as Gaussian Markov random field (MRF) models, are commonly used for gene regulatory network construction. Most current approaches to estimating network structure via GGMs can be categorized into a binary decision that determines if an edge exists through penalized optimization and a probabilistic approach that incorporates graph uncertainty. Analyses in the first category usually adopt the perspective of variable (edge) selection without consideration of probabilistic interpretation. Methods in the second group, particularly the Bayesian approach, often quantify the uncertainty in the network structure with a stochastic measure on the precision matrix. Nevertheless, these methods overlook the existence probability of an edge and its strength related to the dependence between nodes. This study simultaneously investigates the existence and intensity of edges for network structure learning. We propose a method that combines the Bayesian MRF model and conditional autoregressive model for the relationship between gene nodes. This analysis can evaluate the relative strength of the edges and further prioritize the edges of interest. Simulations and a glioblastoma cancer study were carried out to assess the performance of our proposed models and compare it with existing methods. The proposed approach shows stable performance and may identify novel structures with biological insights.

show abstract

Transcriptional Analysis of JAK/STAT Signaling in Glioblastoma Multiforme

Cited by 6 publications

References 0 publications

The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model

The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model

A Review: Phytochemicals Targeting JAK/STAT Signaling and IDO Expression in Cancer

Probabilistic Edge Inference of Gene Networks with Bayesian Markov Random Field Modelling

Contact Info

Product

Resources

About