Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus

Antoszczyk, Slawomir J.; Spyra, Melanie; Mautner, Victor; Kurtz, Armin; Stemmer‐Rachamimov, Anat; Martuza, Robert L.; Rabkin, Samuel D.

doi:10.1093/neuonc/not317

Cited by 32 publications

(41 citation statements)

References 57 publications

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“…Motivated by our in vitro findings, we generated a syngeneic mouse model of MPNST using the M2 cell line in B6129SF1/J mice based on previous literature32 to test the in vivo efficacy of our novel combination therapy. Mice were subcutaneously injected with M2 cells.…”

Section: Resultsmentioning

confidence: 99%

“…The M2 mouse MPNST cell line was a gift from Dr. Samuel A. Rabkin (Massachusetts General Hospital, Harvard Medical School; Boston, Massachusetts)32, originally isolated from spontaneously arising tumors in Nf1/Trp53 heterozygous mice obtained from the LF Parada laboratory. The M2 cells were cultured in DMEM with 10% FBS and 1% Penicillin/Streptavidin (Life Technologies, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether PD901 combined with PBNP-based PTT results in improved treatment outcomes for MPNSTs, we use the mouse M2 MPNST cells in vitro , and a syngeneic, subcutaneous mouse model of MPNST in vivo 32. First, we assess the efficacy of PD901 and PBNP-based PTT individually in treating MPNST cells in vitro .…”

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confidence: 99%

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Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

Sweeney

Burga

et al. 2016

Sci Rep

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

Sweeney

Burga

et al. 2016

Sci Rep

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“…Oncolytic herpes simplex virus selectively infects cells with hyperactive RAS. It has been shown to infect MPNST cells in culture correlating to levels of RAS hyperactivity [148] and inhibit the growth of MPNST cells in immunocompromised mice [149] and immune competent mice [150]. A clinical trial of oncolytic herpes simplex virus therapy for MPNST has recently been opened (NCT00931931).…”

Section: • Oncolytic Virusesmentioning

confidence: 99%

The role of the immune system in neurofibromatosis type 1-associated nervous system tumors

Karmakar

Reilly

2016

CNS Oncol.

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With the recent development of new anticancer therapies targeting the immune system, it is important to understand which immune cell types and cytokines play critical roles in suppressing or promoting tumorigenesis. The role of mast cells in promoting neurofibroma growth in neurofibromatosis type 1 (NF1) patients was hypothesized decades ago. More recent experiments in mouse models have demonstrated the causal role of mast cells in neurofibroma development and of microglia in optic pathway glioma development. We review here what is known about the role of NF1 mutation in immune cell function and the role of immune cells in promoting tumorigenesis in NF1. We also review the therapies targeting immune cell pathways and their promise in NF1 tumors.

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“…Recently, a new orthotopic MPNST model was developed by implantation of mouse NF1 transgenic MPNST cell lines or human NF1 MPNST stem-like cells (MSLCs) into the sciatic nerves of immunocompetent and immunodeficient mice, respectively 57 . In this model, mice develop progressive hind limb deficits, which can be quantified to evaluate treatment efficacy.…”

Section: Oncolytic Virusesmentioning

confidence: 99%

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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Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus

Cited by 32 publications

References 57 publications

Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

The role of the immune system in neurofibromatosis type 1-associated nervous system tumors

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

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