title: 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-1α, 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.
authors.affiliation: Momenta Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: He
authors.initials: H
authors.lastname: Zhou
authors.forename: Sucharita
authors.initials: S
authors.lastname: Roy
authors.forename: Edward
authors.initials: E
authors.lastname: Cochran
authors.forename: Radouane
authors.initials: R
authors.lastname: Zouaoui
authors.forename: Chia Lin
authors.initials: CL
authors.lastname: Chu
authors.forename: Jay
authors.initials: J
authors.lastname: Duffner
authors.forename: Ganlin
authors.initials: G
authors.lastname: Zhao
authors.forename: Sean
authors.initials: S
authors.lastname: Smith
authors.forename: Zoya
authors.initials: Z
authors.lastname: Galcheva-Gargova
authors.forename: Juliane
authors.initials: J
authors.lastname: Karlgren
authors.forename: Nancy
authors.initials: N
authors.lastname: Dussault
authors.forename: Rain Y Q
authors.initials: RY
authors.lastname: Kwan
authors.forename: Erick
authors.initials: E
authors.lastname: Moy
authors.forename: Marishka
authors.initials: M
authors.lastname: Barnes
authors.forename: Alison
authors.initials: A
authors.lastname: Long
authors.forename: Chris
authors.initials: C
authors.lastname: Honan
authors.forename: Yi Wei
authors.initials: YW
authors.lastname: Qi
authors.forename: Zachary
authors.initials: Z
authors.lastname: Shriver
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Ganguly
authors.forename: Birgit
authors.initials: B
authors.lastname: Schultes
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkataraman
authors.forename: Takashi Kei
authors.initials: TK
authors.lastname: Kishimoto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D005434:Flow Cytometry; D006497:Heparan Sulfate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D018716:Molecular Mimicry; D009362:Neoplasm Metastasis; D020349:Surface Plasmon Resonance
chemical_list: D006497:Heparan Sulfate; C562174:M402 heparan sulfate