Momenta Pharmaceuticals, Inc. (MNTA)

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Research Article -

M402, a Novel Heparan Sulfate Mimetic, Targets Multiple Pathways Implicated in Tumor Progression and Metastasis

Abstract:

Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1a, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

Citation: Zhou H, Roy S, Cochran E, Zouaoui R, Chu CL, et al. (2011) M402, a Novel Heparan Sulfate Mimetic, Targets Multiple Pathways Implicated in Tumor Progression and Metastasis. PLoS ONE 6(6): e21106. doi:10.1371/journal.pone.0021106

Editor: John D. Minna, Univesity of Texas Southwestern Medical Center at Dallas, United States of America

Received: February 25, 2011; Accepted: May 19, 2011; Published: June 16, 2011

Copyright: © 2011 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study is funded by Momenta Pharmaceuticals. The funding source does not compromise the objectivity or validity of the research, analyses, and interpretations presented in the paper. The funders had no role in data collection and analysis. The funders approved study designs for some experiments and agreed to the decision to publish the manuscript.

Competing interests: All authors are current or former employees at Momenta Pharmaceuticals, Inc. This employment does not alter the authors' adherence to PLoS ONE policies on sharing data and materials.

* E-mail: [e-mail]

# These authors contributed equally to this work.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0021106