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Top of pageAbstractMalignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Top of pageIntroductionNeurofibromatosis type 1 (NF1) is a tumor predisposition syndrome including benign (neurofibromas) and malignant tumors.
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We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). A main advantage of oncolytic viruses is their ability to replicate selectively within tumor tissue, thereby amplifying the initial dose. Herein we developed and characterized a xenograft model of human MPNST and evaluated the antitumor effects of oHSV mutants (G207 and hrR3) and the EGFR inhibitor, erlotinib. Additive cytotoxicity of these agents was found in human MPNST cell lines, suggesting that EGFR signaling is not critical for virus replication.
Mice bearing human MPNST tumors treated with G207 or hrR3 by intraperitoneal or intratumoral injection showed tumor-selective virus biodistribution, virus replication, and reduced tumor burden. We used the xenograft models to investigate the therapeutic effects of oHSV and erlotinib, alone and in combination. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy.
Both oHSV and erlotinib were antiangiogenic as measured by proangiogenic gene expression, effect on endothelial cells and xenograft vessel density. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients.
Overall, oHSVs showed highly potent antitumor effects against MPNST xenografts, an effect not diminished by EGFR inhibition.
Despite additive inhibition of growth of cultured cells, in vivo combination therapies showed only a trend toward less tumor burden.
Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. STS26T MPNST xenografts were highly vascular (Figure 1a) and showed characteristics of human disease including spindle shaped cells and abundant collagen fiber deposition (Figure 1b and c). Widespread intratumoral virus distribution with fractionated injection enables local control of large human rhabdomyosarcoma xenografts by oncolytic herpes simplex viruses. Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus. Oncolytic herpes simplex virus mutants are more efficacious than wild-type adenovirus for the treatment of high-risk neuroblastomas in preclinical models.
Expression of a majority (72%) of MPNST signature genes was dysregulated in STS26T xenograft tumors relative to NHSC (Figure 1g; Supplementary Table S2). Several genes of known functional significance in MPNST pathogenesis were coordinately regulated between MPNST primary tumors and STS26T xenografts. For example, upregulation of neural crest transcription factors, TWIST1 and SOX9, support maintenance of a stem-like phenotype.
Downregulation of mature Schwann cell markers, including NGFR and PMP22, are characteristic of abnormal differentiation. Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1. Oncolysis of pancreatic tumour cells by a gamma34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway. Whereas normal organs from oHSV-infected mice showed no change in enzymatic activity above PBS-treated mice, tumor homogenates from oHSV-treated mice showed a 245- and 29-fold increase in -galactosidase activity at days 3 and 7, respectively (Figure 2a). Malignant peripheral nerve sheath tumors with high and low Ras-GTP are permissive for oncolytic herpes simplex virus mutants.

Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. Tumors infected by either virus showed tissue destruction that stained positively for HSV antigen and contained inclusion bodies characteristic of HSV infection (Figure 2c–e).
Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib.
HSV antigen positive areas were also positive for HSV DNA by in situ hybridization (Figure 2f).
Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. By day 30, PBS-treated mice developed severe ascites, were less active and contained a large tumor burden. Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST).
Animals receiving lower doses of G207 or hrR3 showed modest reductions in tumor burden illustrating a dose-dependent oHSV effect. Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues.
The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade.
Inhibition of proliferation, migration, and matrix metalloprotease production in malignant mesothelioma cells by tyrosine kinase inhibitors. While the median overall survival of control animals was 35 days, G207 and hrR3-treated groups survived 42 and 44 days, respectively (Figure 3d). To investigate potential mechanisms of tumor cell escape we examined remaining tumor nodules for -galactosidase activity, infectious virus and for cellular resistance to oHSV. Tumor nodules recovered from G207 or hrR3-treated mice showed no -galactosidase activity above baseline and were negative for infectious virus (data not shown).
To determine if these tumors had acquired resistance to lytic infection by oHSV, cell lines were established from recovered tumor nodules. Cell lines from PBS- or virus-treated mice showed similar sensitivity to the parental cell line STS26T (data not shown). Early passage, rapidly dividing human umbilical vein endothelial cells (HUVECs) infected by G207 or hrR3 were efficiently euthanized (Figure 4a), supported robust virus replication on par with wtHSV-1 KOS (Figure 4b) and showed morphologic changes characteristic of HSV-infected cells (Figure 4c and d). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.
Others have shown in a mesothelioma model that EGFR inhibition mediates a decrease in tumor angiogenesis by reduction of vascular endothelial growth factor24 and matrix metalloproteases.25 To test whether these pathways are affected by EGFR inhibition in MPNSTs, signaling through EGFR was inhibited with the small molecule EGFR tyrosine kinase inhibitor erlotinib. When grown in the presence of erlotinib, MPNST cell lines STS26T and S462 showed a reduced expression pattern of proangiogenic genes (Figure 5a) and demonstrated antiproliferative effects (Figure 5b).
Cytotoxicity assay showing effect of erlotinib against (b) MPNST cell lines STS26T and S462 and (c) HUVEC at 2 (), 4 (), and 6 () days post-infection.
When cultured in the presence of erlotinib, the MPNST cell line STS26T showed a significant reduction in EGFR phosphorylation (Figure 6a). STS26T cells treated with the combination of oHSV and erlotinib showed enhancement of cytotoxic effects at days 1, 2, and 4 post-infection (Figure 6b).
Comparison of the treatment regimens that split the total virus dose into four vs three fractions showed a slight improvement. Animals treated with erlotinib alone exhibited a trend in tumor reduction but those treated with oHSV showed highly significant antitumor effects. Coadministration of oHSV and erlotinib in vitro demonstrated that inhibition of EGFR signaling did not adversely affect virus replication; in fact, overall cell killing was enhanced by the combination.
Nevertheless, the potent anti-MPNST activity of oHSV was not enhanced by combination with erlotinib.

MPNST xenograft models that closely resemble human disease as measured by immunostaining and microarray analysis and that should prove useful for testing other experimental therapeutics.
In addition, the model is reproducible and rapidly progressive, facilitating expedited testing of investigational therapeutics. Limitations of the xenograft models include the lack of T-cell immunity as well as the fact that the tumors are not an outgrowth of nerve sheaths, so the tumor microenvironment may not be authentic.Owing to their cytostatic nature, inhibitors of signaling pathways key to MPNST pathogenesis such as erlotinib are unlikely to eradicate existing tumors.
Injection of oHSV into tumors causes reduction of tumor burden by multiple mechanisms, including direct cytoxicity, stimulation of antitumor immune responses29, 30 and inhibition of angiogenesis.22, 23 There are no reports of initially sensitive tumor cell clones acquiring resistance to oHSV. The ability of oHSV to selectively target cells with hyperactive Ras signaling makes oHSV a highly rational candidate for treatment of NF1-associated malignancies.
Tumor-associated neoangiogenesis appears to play an important role in the pathogenesis of NF1-associated malignancies as haploinsufficiency of NF1 augments angiogenesis,31, 32, 33 and angiogenic factors including EGF, vascular endothelial growth factor, Midkine, platelet-derived growth factor and fibroblast growth factor-2 have been identified within neurofibromas.34 Additionally, neurofibroma-derived Schwann cells display angiogenic and invasive properties,35 and MPNSTs are known to be highly vascular. Thus, antiangiogenic properties of erlotinib and oHSV may play a role in their antitumor effects.The fact that combination of oHSV with erlotinib did not show enhancement of the antitumor effect may be explained by a number of non-exclusive hypotheses.
First, a higher dose of erlotinib may be required to observe any enhancement of the oHSV-mediated antitumor effect. It is also possible that MPNST xenografts treated with erlotinib had acquired resistance to erlotinib or lost dependence upon EGFR signaling.
In that case, other factors could bypass a need for EGFR-mediated signaling.In conclusion, our preclinical results demonstrate robust anti-MPNST efficacy of oHSV, alone or in combination with erlotinib. African green monkey kidney cells (Vero), rabbit skin cells and human MPNST cells have been previously described.13 Single donor HUVECs were cultured in EBM plus SingleQuots growth supplements media (Cambrex, Rockland, ME). Normalization of the data included RMA processing, followed by per chip normalization to the median, and per gene normalization to the NHSC samples. Unsupervised hierarchical cluster analysis using Pearson Correlation for a distance metric was used to arrange the 159 genes in the MPNST signature according to similar expression patterns.In vitro and in vivo virus replication assays. Mice were euthanized at indicated times post-infection, tumors harvested, homogenized in PBS and subjected to plaque assay.In vitro viral cytotoxicity assay. Erlotinib, dimethylsulfoxide, G207, hrR3 or combinations were added and incubated at 37°C, 5% CO2. RNA was extracted using Trizol (Invitrogen, Carlsbad, CA) followed by RNeasy (Qiagen, Valencia, CA).
RT–qPCR was performed in DNA Engine Opticon 2 Continuous Fluorescence Detection System (BioRad, Hercules, CA). Sample RNA was processed in triplicate with serial dilutions of Human Universal Reference RNA (Stratagene, La Jolla, CA) on the same 96-well plate.
Graphically, the middle line of the bar represents mean, bar size corresponds to the difference between lower quartile and upper quartile, and error bars represent the range of the raw data. Animal studies were approved by the Cincinnati Children's Hospital Medical Center Institutional Animal Care and Use Committee. At days 3 and 7 post-infection, mice were euthanized, tumor and organs harvested, homogenized and assayed for protein concentration and -galactosidase activity as previously reported.13IHC and in situ hybridization. Tumor vascular density was quantified via blinded counting of the mean number of vessels (identified by CD31+ staining around a lumen) within 10 high power fields ( 400). Protein (30 g) was subjected to denaturing electrophoresis followed by electro-transfer to polyvinylidene fluoride membrane (Biorad). Blots were incubated with secondary anti-rabbit IgG HRP (Amersham Biosciences) and signal detection by Western lightening ECL reagent plus (Perkin-Elmer, Boston, MA).Statistical analysis.

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