The proposed five-year training program is designed to provide the principal investigator with the background in microarray-based genome-wide epigenomic profiling directed towards translational brain cancer research. As an Assistant Professor, the PI is a clinically active neuro-oncologist with designated laboratory space. This training program will enable him to enter a new area of research that is directly synergistic with his clinical efforts as a co-principal investigator on a recently opened UCLA/Genentech clinical trial (target enrollment of 70 patients) evaluating the use of bevacizumab (Avastin) in combination with temozolomide and radiation for patients with newly-diagnosed glioblastoma. Critical determinants in his training program are the mentor, Dr. Stan Nelson, access to the UCLA Neuro-oncology database, and active support of the UCLA brain tumor research environment. Dr. Nelson is a recognized leader in the field of genome-wide array based analysis and has been active in large-scale genetic characterization of patient glioblastoma tissue in the UCLA Neuro-oncology database, a large clinically annotated collection of patient tissue, cell lines, and radiographic images. The potential for powerful correlative studies harnessing this database have been realized by a large number of recent studies from the UCLA group. The overall goal of the research plan is based on the recent discovery that glioblastoma patients whose tumors have O(6)-Methylguanine DNA methyltransferase (MGMT) promoter methylation demonstrate better survival and response to temozolomide (TMZ). This finding emphasizes the importance of aberrant methylation in brain cancer. We hypothesize that genome-wide methylation profiling of glioma will lead to the discovery of novel methylated genes and signatures of coordinately methylated genes, and we demonstrate the feasibility of using differential methylation hybridization (DMH) to achieve these goals.
The specific aims are: 1) to understand the role of promoter methylation in astrocytoma transformation by comparing genome-wide methylation profiles of low grade astrocytomas, anaplastic astrocytomas, primary and secondary glioblastomas, and normal brain samples, 2) to determine genome-wide methylation, gene expression, and loss of heterozygosity (LOH) profiles associated with response to a novel upfront therapy combining bevacizumab with radiation therapy and TMZ, 3) to examine the role of DNA methyltransferase 1 (DNMT1) in glioblastoma methylation by profiling genome-wide methylation changes in glioblastoma cell lines resulting from pharmacologic or genetic modulation of DNMT1 activity. The overall goal of this proposal is to improve therapeutic outcomes for glioma patients by developing personalized approaches based on prospective molecular characterization of tumor samples.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA124479-04
Application #
8131648
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2008-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$136,500
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Piccioni, David E; Selfridge, Julia; Mody, Reema R et al. (2014) Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy. Neuro Oncol 16:815-22
Li, Sichen; Chowdhury, Reshmi; Liu, Fei et al. (2014) Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas. Clin Cancer Res 20:5808-22
Lalezari, Shadi; Chou, Arthur P; Tran, Anh et al. (2013) Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome. Neuro Oncol 15:370-81
Li, Sichen; Chou, Arthur P; Chen, Weidong et al. (2013) Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol 15:57-68
Chou, Arthur P; Chowdhury, Reshmi; Li, Sichen et al. (2012) Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas. J Natl Cancer Inst 104:1458-69
Lai, Albert; Kharbanda, Samir; Pope, Whitney B et al. (2011) Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. J Clin Oncol 29:4482-90
Lai, Albert; Tran, Anh; Nghiemphu, Phioanh L et al. (2011) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29:142-8
Sherman, J H; Aregawi, D G; Lai, A et al. (2009) Optic neuropathy in patients with glioblastoma receiving bevacizumab. Neurology 73:1924-6
Tran, Anh; Escovedo, Cameron; Migdall-Wilson, Justine et al. (2009) In Silico Enhanced Restriction Enzyme Based Methylation Analysis of the Human Glioblastoma Genome Using Agilent 244K CpG Island Microarrays. Front Neurosci 3:57