Abstract
Oncolytic viruses aim to specifically kill tumor cells. A major challenge is the effective targeting of disseminated tumors in vivo. We retargeted herpes simplex virus (HSV) tropism to HER-2 oncoprotein p185, overexpressed in ovary and breast cancers. The HER-2-retargeted R-LM249 exclusively infects and kills tumor cells expressing high levels of human HER-2. Here, we assessed the efficacy of systemically i.p. delivered R-LM249 against disseminated tumors in mouse models that recapitulate tumor spread to the peritoneum in women. The human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally (i.p.) in immunodeficient Rag2⁻/⁻;Il2rg⁻/⁻ mice gave rise to a progressive peritoneal carcinomatosis which mimics the fatal condition in advanced human patients. I.p. administration of R-LM249 strongly inhibited carcinomatosis, resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Intraperitoneal metastases are a common outcome in breast cancer: i.p. administration of R-LM249 strongly inhibited the growth of ovarian metastases of HER-2+ MDA-MB-453 breast cells. Brain metastases were also reduced. Cumulatively, upon i.p. administration the HER-2-redirected oncolytic HSV effectively reduced the growth of ovarian and breast carcinoma disseminated to the peritoneal cavity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / metabolism
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Breast Neoplasms / metabolism
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Breast Neoplasms / mortality
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Breast Neoplasms / therapy*
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Cell Line, Tumor
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Cell Survival
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Female
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Genetic Therapy / methods
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Genetic Vectors / genetics
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Genetic Vectors / metabolism
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Herpesvirus 1, Human / genetics*
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Herpesvirus 1, Human / physiology
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Humans
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Mice
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Mice, Nude
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Molecular Targeted Therapy
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Oncolytic Virotherapy / methods*
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Oncolytic Viruses / genetics*
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Oncolytic Viruses / metabolism
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / mortality
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Ovarian Neoplasms / therapy*
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Peritoneal Neoplasms / mortality
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Peritoneal Neoplasms / secondary
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Peritoneal Neoplasms / therapy*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Survival Rate
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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ERBB2 protein, human
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Receptor, ErbB-2
Grants and funding
This work was supported by the Italian Association for Cancer Research (AIRC), Milan, Italy (projects n. 10353 and 8959); by GR-2008-1135643 grant from the Italian Ministry of Health to L. Menotti, by grants from the Department of Experimental Pathology, University of Bologna (Pallotti funds); by the University of Bologna RFO (Ricerca Fondamentale Orientata); the Italian Ministry for University and Research (PRIN 2008 and 2009 projects); and a grant from Fondazione del Monte di Bologna e Ravenna to G. Campadelli-Fiume. V. Gatta is the recipient of a fellowship from FoRiBiCA Foundation and was also supported through Investigator Grant from AIRC (Associazione Italiana per la Ricerca sul Cancro), Milan, to GCF. V. Grosso is the recipient of a fellowship from FIRC, M. Dall'Ora is the recipient of a PhD fellowship from the University of Bologna. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.