Malignant glioma (Glioblastoma multiforme, GBM, glioma) is the most common and aggressive primary adult brain tumor. The prognosis of GBM patients remains poor, despite surgery, radiation and chemotherapy. Significantly, genes that play a role in neural stem cell maintenance, including BMI1 and SUZ12, are highly expressed in GBM. BMI1 acts as part of the polycomb repressor complex 1 (PRC1) and SUZ12 as a part of PRC2. These complexes play critical role in epigenetic silencing by modifying chromatin structure. PRC1/2 have been shown to contribute to glioma cells tumorigenicity and glioma "stem-like" cells (GSCs) self-renewal. Through their regulation of multiple genes, microRNAs (miRNA) orchestrate complex programs of gene expression and act as master regulators of cellular processes. MiRNA-based therapeutics could thus impact broad cellular programs, leading to cancer cell differentiation, cell cycle arrest, apoptosis, inhibition of invasion and sensitization to radio/chemotherapy. Our data show that miR-128 targets BMI1 and SUZ12 in glioma cells and GSCs. This particular miR is weakly expressed in GBM, and, miR-128 directly targets BMI1 and PRC2 component SUZ12. This simultaneous targeting of both PRCs prevents their partially redundant functions. We demonstrated that miR-128 increases radio-sensitivity of GSCs and, using mouse genetic model of glioma, that loss of miR-128 in early event in gliomagenesis. Therefore, our overall hypothesis is that restoration of the expression of this particular miR in GSCs will result in reduced self-renewal and increased radio- sensitivity through a mechanism that involves members of PRC1/2 complexes. To pursue the validity of this overall hypothesis, we thus propose to:
Aim 1 : Characterize in vitro the influence of miR-128 on therapy sensitization and subsequent cell death in extended panel of GSCs;
Aim 2 : Validate the role of miR-128 in regulation of PRC in mouse genetic models of glioblastoma;
Aim 3 : Determine if miR-128 can be exploited to sensitize glioblastoma to conventional therapies in vivo. Successful completion of the proposed experiments will provide additional mechanistic insights into miR based regulation of PRC's role in gliomagenesis and maintenance and a rationale for the clinical translation of a novel therapeutic strategy using miRs that target members of PRC in GSCs for the treatment of gliomas.

Public Health Relevance

This study attempts to determine a link between expression of certain molecules known as microRNA-128 and cancer stem cells (cancer initiating cells) of glioblastoma, the most lethal brain tumors among adult patients. We plan to test our hypotheses by employing series of in vitro and in vivo experiments involving multiple cancer stem cell lines and animal models of glioblastoma. If our study determines that alterations in selected microRNA-128 expression affect glioblastoma pathogenesis, microRNAs replacement therapy can be developed in the future to improve current glioblastoma treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA176203-01A1
Application #
8817873
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Kondapaka, Sudhir B
Project Start
2014-09-24
Project End
2019-08-31
Budget Start
2014-09-24
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$377,225
Indirect Cost
$164,053
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115