Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin

Zemp, Franz J.; Lun, Xueqing; McKenzie, Brienne; Zhou, Hongyuan; Maxwell, Lori; Sun, Beichen; Kelly, John J.; Stechishin, Owen; Luchman, Artee; Weiss, Samuel; Cairncross, J. Gregory; Hamilton, Mark G.; Rabinovich, Brian A.; Rahman, Masmudur M.; Mohamed, Mohamed R.; Smallwood, Sherin; Senger, Donna L.; Bell, John C.; McFadden, Grant; Forsyth, Peter

doi:10.1093/neuonc/not035

Cited by 42 publications

(62 citation statements)

References 49 publications

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“…Stable BTIC lines expressing enhanced firefly luciferase (effLuc) and eGFP were generated using a self-inactivating lentiviral vector system as described previously (28,29). BT73R and BT206R are temozolomide-resistant BTIC lines generated from parental BT73 and BT206.…”

Section: Btic Lines Tissue Culture and Reagentsmentioning

confidence: 99%

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

164

119

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Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings.

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Section: Btic Lines Tissue Culture and Reagentsmentioning

confidence: 99%

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

164

119

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“…These studies suggest the therapeutic potential of oncolytic viruses against BTSCs; indeed, Delta-24-RGD is currently in phase 1 clinical testing for the treatment of patients with recurrent glioma (U.S. National Institutes of Health). Myxoma virus (MYXV), in combination with rapamycin has been successfully shown to promote anti-tumor activity of BTSCs in mice infected with glioblastoma multiformeted and reduce CD133 expressing stem cells (Zemp, Lun et al 2013). …”

Section: Oncolytic Viral Approaches For Targeting Btscsmentioning

confidence: 99%

Brain Tumor Treatment: 2017 Update

Chakraborty¹,

Han²,

Faltas³

et al. 2018

CCO

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Malignant brain tumors are a heterogeneous group of diseases arising from different cell types that affect both adults and children. The high recurrence rate of malignant brain tumors typically is due to reappearance of focal masses, indicating that a sub population of tumor cells are insensitive to current therapies and may be responsible for reinitiating tumor growth. It is generally agreed that the resistant tumor cells are comprised of cancer stem cells or tumor-initiating cells. While brain tumor stem cells (BTSCs) were first isolated within the last decade, much of the early research has been focused on identifying the BTSC markers and therapeutic targets. The challenge however, is to translate this knowledge to therapeutics. In the current review, we survey the remedial strategies to target BTSCs, which includes diagnostic, pharmacologic, immunologic, viral, and post-transcriptional approaches.

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“…Myxoma virus has been tested in combination with rapamycin and TMZ in vitro and in a murine glioma model grown from patient-derived GSCs [46]. Even TMZ-resistant cells showed susceptibility to myxoma infection and killing, and all treatment groups experienced a survival benefit.…”

Section: Oncolytic Virusesmentioning

confidence: 99%

“…Rapamycin also decreases infiltration of macrophages/microglia, activates Akt and decreases type I IFN production, increasing the infectivity of OVs [46]. Rapamycin's collective immunosuppressive effects allow increased viral replication [110,116].…”

Section: Combination Therapy: Oncolytic Viruses and Chemotherapymentioning

confidence: 99%

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Unlocking the Promise of Oncolytic Virotherapy in Glioma: Combination With Chemotherapy to Enhance Efficacy

et al. 2015

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Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.

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Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin

Abstract: Our study suggests that MYXV in combination with rapamycin infects and kills both the BTICs and the differentiated compartments of GBM and may be an effective treatment even in TMZ-resistant patients.

Cited by 42 publications

References 49 publications

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Brain Tumor Treatment: 2017 Update

Unlocking the Promise of Oncolytic Virotherapy in Glioma: Combination With Chemotherapy to Enhance Efficacy

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