Presentation Title

Addressing the DNA Damage Response to Irradiation and PARP1/PARG Inhibitors in Glioblastoma

Project Collaborators

Dr. Delphine Quenet (Faculty Mentor), Trevor Wolf (Graduate Student Mentor)

Abstract

Grade IV glioblastoma (GBM) is a highly lethal, fast-progressing brain cancer with 2% survival 3 years post-diagnosis. Current treatment includes chemotherapy with the alkylating agent temozolomide (TMZ) and radiotherapy. GBM recurrence is common and associated with TMZ resistance, resulting in 30-week median overall survival post-diagnosis. Novel therapies are needed to increase survival and improve patient quality of life.

Two promising drugs are inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP1) and Poly(ADP-ribose) Glycohydrase (PARG). The enzymatic activities of these proteins involve maintenance of genome integrity and the choice between cell survival and cell death. PARP1 inhibitors have demonstrated cytotoxic effects in various cancers and are FDA-approved for specific subtypes of ovarian cancers. However, the outcomes of inhibiting PARP1 or PARG in GBM are unknown. To address this question, we are comparing the level of DNA damage, integrity of cell division, and cell death pathway activation upon PARP1/PARG inhibition in combination with irradiation. This project will provide knowledge about the role of PARP1 and PARG activity in GBM and the potential therapeutic benefit of targeting these proteins.

Primary Faculty Mentor Name

Dr. Delphine Quenet

Graduate Student Mentors

Trevor Wolf

Status

Undergraduate

Student College

College of Arts and Sciences

Program/Major

Neuroscience

Primary Research Category

Biological Sciences

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Addressing the DNA Damage Response to Irradiation and PARP1/PARG Inhibitors in Glioblastoma

Grade IV glioblastoma (GBM) is a highly lethal, fast-progressing brain cancer with 2% survival 3 years post-diagnosis. Current treatment includes chemotherapy with the alkylating agent temozolomide (TMZ) and radiotherapy. GBM recurrence is common and associated with TMZ resistance, resulting in 30-week median overall survival post-diagnosis. Novel therapies are needed to increase survival and improve patient quality of life.

Two promising drugs are inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP1) and Poly(ADP-ribose) Glycohydrase (PARG). The enzymatic activities of these proteins involve maintenance of genome integrity and the choice between cell survival and cell death. PARP1 inhibitors have demonstrated cytotoxic effects in various cancers and are FDA-approved for specific subtypes of ovarian cancers. However, the outcomes of inhibiting PARP1 or PARG in GBM are unknown. To address this question, we are comparing the level of DNA damage, integrity of cell division, and cell death pathway activation upon PARP1/PARG inhibition in combination with irradiation. This project will provide knowledge about the role of PARP1 and PARG activity in GBM and the potential therapeutic benefit of targeting these proteins.