| Title: |
Combined inhibition of topoisomerase I and poly(ADP-ribose) polymerase: A synergistic therapeutic strategy for glioblastoma with phosphatase and tensin homolog deficiency |
| Authors: |
Kim, Olga; Butler, Madison; Sergi, Zach; Robey, Robert W; Zhang, Meili; Chari, Raj; Pang, Ying; Yu, Guangyang; Zhang, Wei; Song, Hua; Davis, Dionne; Hawley, Robert G; Wen, Xinyu; Wang, Herui; Quezado, Martha; Tran, Bao; Merchant, Mythili; Ranjan, Alice; Furnari, Frank B; Khan, Javed; Gilbert, Mark R; Ryan Miller, Christopher; Gottesman, Michael M; Pommier, Yves; Wu, Jing |
| Contributors: |
National Institutes of Health; Lasker Clinical Research |
| Source: |
Neuro-Oncology Advances ; volume 5, issue 1 ; ISSN 2632-2498 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2023 |
| Description: |
Background Deletions or loss-of-function mutations in phosphatase and tensin homolog (PTEN) are common in glioblastoma (GBM) and have been associated with defective DNA damage repair. Here we investigated whether PTEN deficiency presents a vulnerability to a simultaneous induction of DNA damage and suppression of repair mechanisms by combining topoisomerase I (TOP1) and PARP inhibitors. Methods Patient-derived GBM cells and isogenic PTEN-null and PTEN-WT glioma cells were treated with LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor alone and in combination with a PARP inhibitor, Olaparib or Niraparib. RNAseq analysis was performed to identify treatment-induced dysregulated pathways. Results We found that GBM cells lacking PTEN expression are highly sensitive to LMP400; however, rescue of the PTEN expression reduces sensitivity to the treatment. Combining LMP400 with Niraparib leads to synergistic cytotoxicity by inducing G2/M arrest, DNA damage, suppression of homologous recombination-related proteins, and activation of caspase 3/7 activity significantly more in PTEN-null cells compared to PTEN-WT cells. LMP400 and Niraparib are not affected by ABCB1 and ABCG2, the major ATP-Binding Cassette (ABC) drug efflux transporters expressed at the blood-brain barrier (BBB), thus suggesting BBB penetration which is a prerequisite for potential brain tumor treatment. Animal studies confirmed both an anti-glioma effect and sufficient BBB penetration to prolong survival of mice treated with the drug combination. Conclusions Our findings provide a proof of concept for the combined treatment with LMP400 and Niraparib in a subset of GBM patients with PTEN deficiency. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/noajnl/vdad102 |
| DOI: |
10.1093/noajnl/vdad102/51176613/vdad102.pdf |
| Availability: |
https://doi.org/10.1093/noajnl/vdad102; https://academic.oup.com/noa/advance-article-pdf/doi/10.1093/noajnl/vdad102/51176613/vdad102.pdf; https://academic.oup.com/noa/article-pdf/5/1/vdad102/51531730/vdad102.pdf |
| Accession Number: |
edsbas.40940D80 |
| Database: |
BASE |