On-target JAK2/STAT3 inhibition slows disease progression in orthotopic xenografts of human glioblastoma brain tumor stem cells

Stechishin, Owen D.M.; Luchman, H. Artee; Ruan, Yibing; Blough, Michael; Nguyen, Stephanie; Kelly, John J.; Cairncross, J. Gregory; Weiss, Samuel

doi:10.1093/neuonc/nos302

Cited by 94 publications

(85 citation statements)

References 22 publications

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“…Tumor tissue was frozen at À80 C for molecular analysis or used to culture BTICs as previously described (11)(12)(13)(14). In brief, BTIC lines were initiated in defined culture serum-free medium (SFM).…”

Section: Methodsmentioning

confidence: 99%

Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

Nguyen

Stechishin

Luchman

et al. 2014

Clinical Cancer Research

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Purpose: The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor-initiating cell lines (BTIC).Experimental Design: MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O 6 -benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts. Results: We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-na€ ve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status.Conclusions: These data demonstrate that endogenous MSH6 mutations may be present before alkylator therapy and occur in at least two histologic subtypes of adult glial neoplasms, with this report serving as the first to note these mutations in oligodendroglioma. These findings broaden our understanding of the clinical response to temozolomide in gliomas. Clin Cancer Res; 20(18); 4894-903. Ó2014 AACR.

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Section: Methodsmentioning

confidence: 99%

Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

Nguyen

Stechishin

Luchman

et al. 2014

Clinical Cancer Research

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“…BTIC147 spheres were dissociated to single-cell suspensions, and 1 Â 10 5 cells were stereotactically implanted into the right striata of 6-to 8-week-old NOD/SCID mice as previously described (18,23). Fourteen days after BTIC implantation, mice were randomized to vehicle or treatment cohorts.…”

Section: Intracranial Btic Xenograftsmentioning

confidence: 99%

Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival

Luchman

Stechishin

Nguyen

et al. 2014

Clinical Cancer Research

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Purpose: The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor-initiating cell (BTIC) lines with different combinations of endogenous EGFR wild-type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ)Experimental Design: In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan-Meier survival studies were performed with AZD8055 and in combination with TMZ.Results: We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival.

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“…6 Western blot analyses showed equipotent suppression of pSTAT3 at 1 μM. In a cytotoxicity assay, 31 was found to be more potent (30M, 31 IC 50 = 0.43 μM, cf.…”

mentioning

confidence: 96%

“…Cell viability following drug treatment was assessed after 72 h using an alamarBlue assay. 6,21 IC 50 values were derived and compared to BP-1-102. Consistent with previous findings, BP-1-102 exhibited low micromolar activity ( Figure 2A).…”

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confidence: 99%

Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

Haftchenary

et al. 2013

ACS Med. Chem. Lett.

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ABSTRACT:The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood−brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.

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On-target JAK2/STAT3 inhibition slows disease progression in orthotopic xenografts of human glioblastoma brain tumor stem cells

Abstract: Our study demonstrates the in vitro and in vivo efficacy of on-target JAK2/STAT3 inhibition in heterogeneous BTSC lines that closely emulate the genomic and tumorigenic characteristics of human GBM.

Cited by 94 publications

References 22 publications

Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival

Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

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