Glioblastoma multiforme (GBM) is the most malignant form of brain tumors with more than 18,000 newly diagnosed patients and 13,000 deaths annually in the United States. The prognosis for GBM remains dismal with a median survival time of GBM patients of 14 to 16 months after diagnosis. A hallmark of malignant GBM is their high heterogeneity within the tumors. This unique characteristic manifests to molecular subtypes of GBM that display unique patterns of pathogenesis, biology, and prognosis. While specific molecular markers are of value in clinical care (e.g., IDH1/2 mutations, 1p/19q co-deletion), significant improvement in prognostic stratification and targeted therapeutics are urgently needed. With the ultimate goal of realizing the full potential of personalized and precision medicine, we propose to interrogate long non-coding RNAs (lncRNAs) in a cohort of clinical GBM specimens. LncRNAs are a class of non-coding RNAs that have emerged as critical modulators in various cellular processes through gene regulation. Previous studies including The Cancer Genome Atlas (TCGA), though limited by their profiling technique not designed for non-coding RNAs, have suggested that lncRNAs are abundant in human cancers and are highly cancer-type-specific. In particular, lncRNAs have been implicated in brain function and glioma development. Specifically, in this exploratory project, we will apply the Ribo-Zero-based transcriptomic sequencing (RNA-seq) to comprehensively characterize lncRNAs in 100 clinical GBM samples that have been collected at the Northwestern University Brain Tumor Tissue Bank (Aim 1a). In contrast to the oligo(dT)-based RNA-seq that was used by previous studies, including TCGA, the Ribo-Zero-based technique is optimized for non-coding RNA transcripts, thus offering a great advantage for profiling all potentially functional lncRNAs in GBM. Notably, a novel detection algorithm based on machine learning will be developed to provide a more flexible and universal framework of lncRNA detection using RNA-seq. Though restricted to those lncRNAs shared between our GBM data and the oligo(dT)-based TCGA, we will evaluate the tissue-specificity of lncRNAs detected in GBM using TCGA data on several solid tumors (Aim 1b). After characterizing the landscape of lncRNAs in GBM, we will evaluate whether lncRNAs are associated with the clinical outcomes of GBM patients, and evaluate the feasibility of integrating lncRNAs and gene-level transcripts into a prognostic tool (Aim 2a). This proposal will enable us to employ these novel biomarkers for the prognosis of GBM as well as future functional studies. In addition, we will utilize co-expression network analysis to assign functions to the detected lncRNAs in GBM. An integrated, internet-based catalog will be constructed to provide a resource of lncRNAs in GBM that will benefit the general research community in this new area (Aim 2b). Finally, the PIs have assembled an outstanding research team with significant achievements in relevant research areas and complimentary expertise, therefore ensuring the success of this multidisciplinary and highly innovative project.

Public Health Relevance

This work seeks to understand whether long non-coding RNAs implicate in the prognosis of glioblastoma multiforme (GBM), a form of malignant brain tumors. By characterizing these novel gene regulatory molecules in GBM, we expect to identify novel biomarkers that can be used as a prognostic tool for patients with GBM. This approach could also be applied to other human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA209345-02
Application #
9321295
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Ganguly, Aniruddha
Project Start
2016-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Bell, Jonathan B; Eckerdt, Frank; Dhruv, Harshil D et al. (2018) Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation. Mol Cancer Res 16:32-46
Sang, Youzhou; Li, Yanxin; Song, Lina et al. (2018) TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3. Cancer Res 78:1792-1804
Wang, Wei; Zhang, Honghong; Liu, Sali et al. (2017) Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A. Proc Natl Acad Sci U S A 114:8366-8371
Xing, Fan; Luan, Yizhao; Cai, Jing et al. (2017) The Anti-Warburg Effect Elicited by the cAMP-PGC1? Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes. Cell Rep 18:468-481
Huang, Tianzhi; Kim, Chung Kwon; Alvarez, Angel A et al. (2017) MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. Cancer Cell 32:840-855.e8
Lv, Deguan; Li, Yanxin; Zhang, Weiwei et al. (2017) TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma. Nat Commun 8:1454
Lv, Deguan; Jia, Feng; Hou, Yanli et al. (2017) Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding. Cancer Res 77:6190-6201
Hashizume, Rintaro; Zhang, Ali; Mueller, Sabine et al. (2016) Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. Neuro Oncol 18:1519-1528
Huang, Tianzhi; Alvarez, Angel A; Pangeni, Rajendra P et al. (2016) A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways. Nat Commun 7:12885
Bell, Jonathan B; Eckerdt, Frank D; Alley, Kristen et al. (2016) MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma. Mol Cancer Res 14:984-993

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