Oncolytic HSV and Erlotinib Inhibit Tumor Growth and Angiogenesis in a Novel Malignant Peripheral Nerve Sheath Tumor Xenograft Model

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Testing of therapeutics for MPNST has been hampered by lack of adequate xenograft models. We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). 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. oHSV injection demonstrated more dramatic antitumor activity than erlotinib. Combination therapies showed a trend toward an increased antiproliferative effect. Both oHSV and erlotinib were antiangiogenic as measured by proangiogenic gene expression, effect on endothelial cells and xenograft vessel density. Overall, oHSVs showed highly potent antitumor effects against MPNST xenografts, an effect not diminished by EGFR inhibition. Our data suggest that inclusion of MPNSTs in clinical trials of oHSV is warranted.

Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors

“…Of the eight MPNST cell lines, STS26T is the only one that grows consistently as a xenograft in athymic nude nu/nu mice (35). In this model, tumors reach 10% body weight f1 month after injection and these tumors have similar histopathologic features as MPNST found in human patients (35).…”

“…In accordance with our animal protocol, mice were sacrificed when tumor size reached 10% body weight (f3,000 mm 3 ; ref. 35). Tumors were dissected and either flash frozen and stored at À80jC or fixed in 10% formalin and embedded in paraffin.…”

Malignant peripheral nerve sheath tumours of the spine: clinical manifestations, classification, treatment, and prognostic factors

“…Quite clearly more effective approaches are needed for treating spinal MPSNTs. As the molecular pathways involved in the pathogenesis of MPSNTs are elucidated [19][20][21][22], specific treatments targeting these pathways will hopefully be developed. Further, the use of more sophisticated radiotherapy approaches such as intensity-modulated radiation therapy may also prove to decrease recurrence and increase survival in patients with spinal MPSNTs.…”

An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation

“…In fact, xenograft models have already been used to study therapeutic effects in intraperitoneal and subcutaneous model systems. [12][13][14] Although useful for studying therapeutic effects on in vivo tumor growth, these models do not recapitulate the complex neural microenvironment found in human NF1 MPNSTs. Using a simple and reproducible xenografting technique, we have established a mouse model for intraneural NF1 MPNST applicable for practical therapeutic testing in a relevant cellular environment.…”

“…Although not perfect models, xenografts have been and continue to be used extensively to study human tumor cell growth and to test potential therapeutics. Although a number of useful xenograft models have been used to test therapeutic treatments, [12][13][14] none has shown true intraneural tumor growth closely resembling human NF1 MPNSTs. However, xenografts of human NF1 tumor cells have been shown to persist when injected into scid mouse sciatic nerves, 15 and have recently been shown to recapitulate NF1 plexiform neurofibromas.…”