Dana Farber Cancer Institute

“Inhibition of ATM and CHK2 as Treatment for Glioblastoma Multiforme”

Dr. D’Andrea’s study will evaluate whether malignant gliomas can be effectively treated with drugs that inhibit DNA repair.  The goal of this work is to develop new forms of chemotherapy for the treatment of this disease.

The particular type of chemotherapy Dr. D’Andrea and his team are developing is designed to inhibit the process of DNA repair (a collection of cellular processes by which a cell identifies and corrects damages to the DNA).  During normal cell growth, DNA is subject to damage by normal metabolic activities as well as environmental factors, like ionizing radiation. Without repair, many of these damages will trigger cell death. To prevent this from occurring, cells possess processes designed to recognize and correct damaged DNA. 

It has been demonstrated that oncogenic activation during tumor progression is associated with increased DNA damage accumulation.  Dr. D’Andrea believes the significance of this observation is that, compared to normal cells, tumor cells exhibit increased reliance on or addiction to DNA repair pathways for their continued growth.

Dr. D’Andrea and his team have found that glioma cells with abnormal Epidermal Growth Factor Receptor (EGFR) activation exhibited increased activation of the ATM-CHK2 DNA damage response/repair pathway. He theorizes that the selective killing of these glioma cells can therefore be achieved by inhibition of the ATM-CHK2 pathway. The goal of this study is to determine whether the results observed in tissue culture will also be replicated in vivo in mouse xenograft models as well as in human tumor specimens as a first step toward advancing to a clinical trial in GBM patients.

Dr. D’Andrea and his team will evaluate DNA repair as a target for glioma therapy and determine whether drugs that inhibit DNA repair are promising candidate therapies for the treatment of malignant gliomas.






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