The research team led by Prof. Do Hyun NAM was selected for the National Research Project by the Ministry of Health and Welfare in 2009. From that time, the team developed the idea of ‘AVATAR MOUSE’ and created ‘AVATAR SCAN’ which is the chemical screening system for cancer stem cells. They also produced ‘AVATAMED’ software in order to know the sensitivity experienced by the patient from certain chemical treatment.

Through diligent research activities, the research team developed the analyses of patterns on the genomic mutation depending on the tumor reoccurrence location and its evolutionary patterns. They also proposed optimum target therapies of brain tumor genes.

By proposing new target therapies for brain tumor patients, this research is receiving great expectation in the hopes of providing more precise treatments for brain cancer.   

1. Analyses of patterns on the genomic mutation depending on the tumor reoccurrence location

Here, the research team introduces the genomic analyses of the initial and recurrent tumor specimens from each of 38 GBM patients. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor.

In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk for TMZ-induced hypermutation for these tumors under the standard regimen.

This study was published in 2015 September edition of the Journal Cancer Cell under the research title of ‘Spatiotemporal evolution of the Primary Glioblastoma Genome.’

2. Analysis of evolutionary patter of patients suffering from brain tumors

With Prof. Raul Rabadan of Columbia University in US, the research team analyzed longitudinal genomic and transcriptomic data from 114 patients living in US, Kora, and Italia.

The analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature.

They also find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-b. Silencing LTBP4 in GBM cells leads to suppression of TGF-b activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-b pathway as a potential therapeutic target in GBM.

This study was published in the 2016 June edition of the Journal Nature Genetics under the title of ‘Clonal evolution of glioblastoma under therapy.’

3. Proposed optimum target therapies of brain tumor genes 

On the basis of comprehensive bulk and single-cell analyses, the research team has proposed a multiverse model to interpret the evolu­tion of multiple GBMs.

They studied genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM). Using bulk and single-cell data, they found that samples from the same tumor mass share genomic and expression signatures, whereas geographically separated, multifocal tumors and/or long-term recurrent tumors are seeded from different clones.

They also showed that M-GBMs are more geneti­cally diverse than locally adjacent tumors and that genetic similarity between multiregion samples is associated with consistent drug response.

Specifically, they found an enrichment of PIK3CA mutations in M-GBMs, and found that inhibitors of the PAM pathway are more effective in PDCs from this cohort. These findings support the truncal-target hypothesis, which states that truncal mutations can inform more effective therapies.

This study was published in the 2017 March edition of the Journal Nature Genetics under the title of ‘Spatiotemporal genomic architecture informs precision oncology in glioblastoma.’