Ras Signaling Influences Permissiveness of Malignant Peripheral Nerve Sheath Tumor Cells to Oncolytic Herpes

Farassati, Faris; Pan, Weihong; Yamoutpour, Farnaz; Henke, Susann; Piedra, Mark P.; Frahm, Silke; Al-Tawil, Said; Mangrum, Wells I.; Parada, Luis F.; Rabkin, Samuel D.; Martuza, Robert L.; Kurtz, Armin

doi:10.2353/ajpath.2008.080376

Cited by 30 publications

(24 citation statements)

References 69 publications

(50 reference statements)

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“…N-Ras (G12V) activation in 15N cells was found to increase phosphorylation of ERK1,2 and JNK. This supports previous reports that MPNST cell lines with high Ras-GTP had increases in ERK and JNK signaling pathways compared to cells with low Ras-GTP [47]. We also observed that when N-Ras (G12V) was induced in 15N and 10N cells AP-1 transcriptional activity was increased up to 1.7-fold.…”

Section: Discussionsupporting

confidence: 92%

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors

et al. 2010

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Plexiform neurofibromas commonly found in patients with Neurofibromatosis type I (NF1) have a 5% risk of being transformed into malignant peripheral nerve sheath tumors (MPNST). Germline mutations in the NF1 gene coding for neurofibromin, which is a Ras GTPase activating protein (RasGAP) and a negative regulator of Ras, result in an upregulation of the Ras pathway. We established a direct connection between neurofibromin deficiency and downstream effectors of Ras in cell lines from MPNST patients by demonstrating that knockdown of NF1 expression using siRNA in a NF1 wild type MPNST cell line, STS-26T, activates the Ras/ERK1,2 pathway and increases AP-1 binding and activity. We believe this is the first time the transactivation of AP-1 has been linked directly to neurofibromin deficiency in a disease relevant MPNST cell line. Previously, we have shown that N-Ras is constitutively activated in cell lines derived from independent MPNSTs from NF1 patients. We therefore sought to analyze the role of the N-Ras pathway in deregulating AP-1 transcriptional activity. We show that STS-26T clones conditionally expressing oncogenic N-Ras show increased phosphorylated ERK1,2 and phosphorylated JNK expression concomitant with increased AP-1 activity. MAP kinase pathways (ERK1,2 and JNK) were further examined in ST88-14, a neurofibromin-deficient MPNST cell line. The basal activity of ERK1,2 but not JNK was found to increase AP-1 activity. These experiments further confirmed the link between the loss of neurofibromin and increased activity of Ras/MAP kinase pathways and the activation of downstream transcriptional mechanisms in MPNSTs from NF1 patients.

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Section: Discussionsupporting

confidence: 92%

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors

et al. 2010

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“…12). These observations imply that paramyxovirus-resistant host cells have an elevated pAKT level but less ERK activation and that differential Ras activation modulates the permissibility to viral fusion (16,17,49). Thus, our observations establish a new framework for redefining the host cell susceptibility or resistance to a given virus and thereby reveal a novel therapeutic strategy.…”

Section: Discussionmentioning

confidence: 96%

Reciprocal Regulation of AKT and MAP Kinase Dictates Virus-Host Cell Fusion

Sharma

Mani

Nandwani

et al. 2010

J Virol

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“…Initial studies in vitro , showed that a set of human MPNST cell lines were sensitive to oHSV G207 and hrR3 (Table 1), regardless of Ras activation, whereas normal human Schwann cells were not permissive to virus replication 52 . In contrast, the susceptibility of mouse MPNST cells isolated from transgenic mouse tumors to G207 was dependent upon elevated levels of Ras activation 53 . Both G207 and hrR3 were able to inhibit tumor growth and survival after intraperitoneal injection of mice bearing intraperitoneal xenografts of human STS26T MPNST 54 .…”

Section: Oncolytic Virusesmentioning

confidence: 90%

Prospects and progress of oncolytic viruses for treating peripheral nerve sheath tumors

Antoszczyk

Rabkin

2015

Expert Opinion on Orphan Drugs

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Introduction Peripheral nerve sheath tumors (PNSTs) are an assorted group of neoplasms originating from neuroectoderm and growing in peripheral nerves. Malignant transformation leads to a poor prognosis and is often lethal. Current treatment of PNSTs is predominantly surgical, which is often incomplete or accompanied by significant loss of function, in conjunction with radiotherapy and/or chemotherapy, for which the benefits are inconclusive. Oncolytic viruses (OVs) efficiently kill tumor cells while remaining safe for normal tissues, and are a novel antitumor therapy for patients with PNSTs. Areas covered Because of the low efficacy of current treatments, new therapies for PNSTs are needed. Pre-clinically, OVs have demonstrated efficacy in treating PNSTs and perineural tumor invasion, as well as safety. We will discuss the various PNSTs and their preclinical models, and the OVs being tested for their treatment, including oncolytic herpes simplex virus (HSV), adenovirus (Ad), and measles virus (MV). OVs can be ‘armed’ to express therapeutic transgenes or combined with other therapeutics to enhance their activity. Expert opinion Preclinical testing of OVs in PNST models has demonstrated their therapeutic potential and provided support for clinical translation. Clinical studies with other solid tumors have provided evidence that OVs are safe in patients and efficacious. The recent successful completion of a phase III clinical trial of oncolytic HSV paves the way for oncolytic virotherapy to enter clinical practice.

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Ras Signaling Influences Permissiveness of Malignant Peripheral Nerve Sheath Tumor Cells to Oncolytic Herpes

Cited by 30 publications

References 69 publications

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors

Reciprocal Regulation of AKT and MAP Kinase Dictates Virus-Host Cell Fusion

Prospects and progress of oncolytic viruses for treating peripheral nerve sheath tumors

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