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Potential of GSPT1 as a novel target for glioblastoma therapy
Takashi Sasayama1, Takeshi Hamada2, Kazuhiro Tanaka1
1Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Abstract:
Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We previously reported that G1 to S phase transition 1 (GSPT1) depletion induces delayed cell cycle in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to the CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with wild-type (WT) U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors with transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those with transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics.
Insights
Glioblastoma (GBM) treatment needs innovation. Targeting GSPT1 (G1 to S phase transition 1) protein with CC-885 drug significantly extended survival in mice, suggesting GSPT1 as a potential therapeutic target for GBM.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Glioblastoma (GBM) remains a lethal brain cancer with limited treatment advancements.
- Glioblastoma (GBM) survival rates have stagnated over three decades, necessitating novel therapeutic strategies.
- G1 to S phase transition 1 (GSPT1) depletion was previously shown to delay cell cycle progression in astrocytes.
Purpose of the Study:
- To investigate the therapeutic potential of targeting GSPT1 in glioblastoma (GBM).
- To evaluate the efficacy of CC-885, a GSPT1-degrading agent, in a preclinical glioblastoma (GBM) model.
Main Methods:
- Administration of CC-885, a cereblon modulator that degrades GSPT1, to mice bearing U87 glioblastoma xenografts.
- Generation and utilization of GSPT1-knockout (KO) U87 cells and GSPT1-rescued cells in mouse xenograft models.
- Assessment of apoptosis via cleaved PARP1 in GSPT1-KO and wild-type (WT) U87 cells and tumors.
Main Results:
- CC-885 treatment significantly prolonged survival in mice with glioblastoma (GBM) xenografts.
- GSPT1-KO U87 cell xenografts showed significantly longer survival and enhanced apoptosis compared to WT and rescued cells.
- GSPT1 expression was detected in human glioblastoma samples, but mRNA levels did not correlate with overall survival.
Conclusions:
- GSPT1 is crucial for glioblastoma (GBM) cell growth and survival.
- Targeting GSPT1, for example, with CC-885, represents a promising therapeutic strategy for glioblastoma (GBM).
- While essential for growth, GSPT1's role in glioblastoma (GBM) malignancy warrants further investigation.
