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Targeting JNK for therapeutic depletion of stem-like glioblastoma cells.

Matsuda K, Sato A, Okada M, Shibuya K, Seino S, Suzuki K, Watanabe E, Narita Y, Shibui S, Kayama T, Kitanaka C - Sci Rep (2012)

Bottom Line: Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies.To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit.Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, 990-9585, Japan.

ABSTRACT
Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells.

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Prevention of brain tumour formation by stem-like glioblastoma cells via transient, systemic administration of JNK inhibitor.Kaplan-Meier plots showing survival of mice (5 mice per group) implanted intracranially with 1×104 stem-like glioblastoma cells ((a) TGS01, (b) GS-Y01, (c) TGS04, and (d) U87GS) followed by transient, systemic administration (intraperitoneal delivery, once daily for 10 consecutive days) of SP600125 (40 mg/kg/day) or the control vehicle (DMSO). Drug administration began on the next day of intracranial implantation. *P < 0.05.
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f5: Prevention of brain tumour formation by stem-like glioblastoma cells via transient, systemic administration of JNK inhibitor.Kaplan-Meier plots showing survival of mice (5 mice per group) implanted intracranially with 1×104 stem-like glioblastoma cells ((a) TGS01, (b) GS-Y01, (c) TGS04, and (d) U87GS) followed by transient, systemic administration (intraperitoneal delivery, once daily for 10 consecutive days) of SP600125 (40 mg/kg/day) or the control vehicle (DMSO). Drug administration began on the next day of intracranial implantation. *P < 0.05.

Mentions: The inhibitory effect of systemic administration of SP600125 on the JNK activity in the brain parenchyma has been well documented in the context of treatment models for various neurological conditions2223. In consideration of this fact, we examined, finally, whether SP600125 administered intraperitoneally deprives orthotopically implanted stem-like glioblastoma cells of their tumour-initiating potential to the extent necessary to provide a survival benefit. The results of pilot orthotopic xenograft experiments involving implantation of serially diluted stem-like glioblastoma cells suggested that reduction of the quantity of stem-like cells by one order of magnitude results in only negligible or minimal survival benefit, depending on the cell line and experimental condition (Supplementary Fig. 14). Therefore, we intensified the SP600125 treatment protocol by extending the treatment period (10 consecutive days instead of 5), with the daily dose fixed at 40 mg/kg/day. When mice that had undergone intracerebral implantation of TGS01 stem-like glioblastoma cells (1×104) were treated with either the control vehicle or SP600125 in accordance with this new, 10-day protocol, survival was significantly enhanced by the SP600125 treatment compared to the control treatment (Fig. 5a). Specifically, SP600125 treatment extended the median survival time by 30 days (22 days for control vs. 52 days for SP600125), suggesting that it had reduced the tumour-initiating population by more than 2 orders of magnitude (Fig. 5a; also see Supplementary Fig. 14 for reference). In line with the in vitro data showing that JNK is required for the maintenance of the stem-like properties in all the stem-like glioblastoma cells tested (Fig. 2 and Supplementary Figs. 5–8), significant survival benefits (roughly estimated to reflect a 10- to 100-fold reduction in the tumour-initiating population) were also observed in all similar orthotopic xenograft experiments conducted thus far using other patient-derived (GS-Y01 and TGS04; Fig. 5b and 5c, respectively) and conventional cell-line derived (U87GS; Fig. 5d) stem-like glioblastoma cells. In a parallel experiment, cohorts of mice not undergoing the implantation procedure were treated with either the control vehicle or SP600125 according to the 10-day protocol to monitor any possible adverse events. All mice survived beyond 12 months after treatment, with no significant differences found in general health status as assessed by body weight and survival (Supplementary Fig. 15) and in cognitive function as assessed by Y-maze test (Supplementary Fig. 16) between the control and SP600125 treatment groups.


Targeting JNK for therapeutic depletion of stem-like glioblastoma cells.

Matsuda K, Sato A, Okada M, Shibuya K, Seino S, Suzuki K, Watanabe E, Narita Y, Shibui S, Kayama T, Kitanaka C - Sci Rep (2012)

Prevention of brain tumour formation by stem-like glioblastoma cells via transient, systemic administration of JNK inhibitor.Kaplan-Meier plots showing survival of mice (5 mice per group) implanted intracranially with 1×104 stem-like glioblastoma cells ((a) TGS01, (b) GS-Y01, (c) TGS04, and (d) U87GS) followed by transient, systemic administration (intraperitoneal delivery, once daily for 10 consecutive days) of SP600125 (40 mg/kg/day) or the control vehicle (DMSO). Drug administration began on the next day of intracranial implantation. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3400080&req=5

f5: Prevention of brain tumour formation by stem-like glioblastoma cells via transient, systemic administration of JNK inhibitor.Kaplan-Meier plots showing survival of mice (5 mice per group) implanted intracranially with 1×104 stem-like glioblastoma cells ((a) TGS01, (b) GS-Y01, (c) TGS04, and (d) U87GS) followed by transient, systemic administration (intraperitoneal delivery, once daily for 10 consecutive days) of SP600125 (40 mg/kg/day) or the control vehicle (DMSO). Drug administration began on the next day of intracranial implantation. *P < 0.05.
Mentions: The inhibitory effect of systemic administration of SP600125 on the JNK activity in the brain parenchyma has been well documented in the context of treatment models for various neurological conditions2223. In consideration of this fact, we examined, finally, whether SP600125 administered intraperitoneally deprives orthotopically implanted stem-like glioblastoma cells of their tumour-initiating potential to the extent necessary to provide a survival benefit. The results of pilot orthotopic xenograft experiments involving implantation of serially diluted stem-like glioblastoma cells suggested that reduction of the quantity of stem-like cells by one order of magnitude results in only negligible or minimal survival benefit, depending on the cell line and experimental condition (Supplementary Fig. 14). Therefore, we intensified the SP600125 treatment protocol by extending the treatment period (10 consecutive days instead of 5), with the daily dose fixed at 40 mg/kg/day. When mice that had undergone intracerebral implantation of TGS01 stem-like glioblastoma cells (1×104) were treated with either the control vehicle or SP600125 in accordance with this new, 10-day protocol, survival was significantly enhanced by the SP600125 treatment compared to the control treatment (Fig. 5a). Specifically, SP600125 treatment extended the median survival time by 30 days (22 days for control vs. 52 days for SP600125), suggesting that it had reduced the tumour-initiating population by more than 2 orders of magnitude (Fig. 5a; also see Supplementary Fig. 14 for reference). In line with the in vitro data showing that JNK is required for the maintenance of the stem-like properties in all the stem-like glioblastoma cells tested (Fig. 2 and Supplementary Figs. 5–8), significant survival benefits (roughly estimated to reflect a 10- to 100-fold reduction in the tumour-initiating population) were also observed in all similar orthotopic xenograft experiments conducted thus far using other patient-derived (GS-Y01 and TGS04; Fig. 5b and 5c, respectively) and conventional cell-line derived (U87GS; Fig. 5d) stem-like glioblastoma cells. In a parallel experiment, cohorts of mice not undergoing the implantation procedure were treated with either the control vehicle or SP600125 according to the 10-day protocol to monitor any possible adverse events. All mice survived beyond 12 months after treatment, with no significant differences found in general health status as assessed by body weight and survival (Supplementary Fig. 15) and in cognitive function as assessed by Y-maze test (Supplementary Fig. 16) between the control and SP600125 treatment groups.

Bottom Line: Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies.To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit.Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, 990-9585, Japan.

ABSTRACT
Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells.

Show MeSH
Related in: MedlinePlus