Targeting the G2/M Checkpoint in Glioblastoma with a Combined Loss of TP53 and CDKN2A
Abstract
Glioblastoma (GBM) is a malignant brain cancer and is almost universally lethal. Every year, around 10,000 new cases of GBM are diagnosed in the United States alone. The first line of treatment against GBM is surgical resection of the tumor, followed by chemotherapy and radiation therapy. However, the cancer always grows back after these standard therapies, and there is no effective treatment yet following cancer recurrence, greatly affecting the survival rate of the patients. Based on a large-scale data analysis of 78 GBM cancer cell lines, we categorized GBMs on the basis of specific genetic changes, as present in the cancer. Our analysis indicate that certain drugs are more effective against a sub-group of GBMs bearing certain mutations, while it is less effective against the other sub-groups. We believe that the limited therapeutic response observed in GBM patients until now is due to lack of consideration of these biomarkers before determining the treatment strategies. Our preliminary analysis suggests that GBMs bearing simultaneous mutations in two genes, TP53 and CDKN2A, will most likely respond to a class of drugs controlling cell cycle progression. The first step in testing our prediction will be to study the effect of the class of drugs in the cells derived from human GBMs bearing these specific mutations, in selective killing of the tumor cells. We will test our hypothesis in the cells with these specific mutations generated using genetic engineering either in laboratory-grown cells or in mice. We also hope to learn how the drugs are working in the cell to induce selective killing. This will potentially provide us a treatment strategy for newly diagnosed GBM patients. We further want to learn whether this class of drugs are effective against GBM in other genetic settings when used together with radiation therapy. We will follow up to evaluate how the cells are dying under these specific treatment conditions and confirm the effects also in mice. Furthermore, we will develop strategies to identify other potential vulnerabilities in presence of this class of drugs, so that we can explore additional therapeutic strategies. In summary, the experiments proposed in this study will allow us to test the effectiveness of the drugs against different sub-groups of GBM, evaluate any synergistic response of the drugs with a standard available GBM therapy, and provide us with new targets that can be explored therapeutically to develop cures against GBM. Successful completion of the aims will also help the PI in acquiring required expertise and experience to develop and execute independent projects aimed to find cures against different sub-types of brain tumors, for which the treatment options are still limited, and to launch her independent scientific career.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910452
Entities
People
- Sangita Pal
Organizations
- Dana–Farber Cancer Institute
- United States Army