title: Targeting the IGF-1R using picropodophyllin in the therapeutical 5T2MM mouse model of multiple myeloma: beneficial effects on tumor growth, angiogenesis, bone disease and survival.
abstract: During the last decade, a central role for insulin-like growth factor 1 (IGF-1) in the pathophysiology of multiple myeloma (MM) has been well established. IGF-I provided by the tumor-microenvironment interaction may directly and indirectly facilitate the migration, survival and expansion of the MM cells in the bone marrow (BM). The inhibition of the IGF-1R-mediated signaling pathway has recently been suggested to be a possible new therapeutic principle in MM. Using the mouse 5T2MM model, we now demonstrate that targeting the IGF-1R using picropodophyllin (PPP) in a therapeutical setting not only has strong antitumor activity on the established MM tumor but also influences the BM microenvironment by inhibiting angiogenesis and bone disease, having a profound effect on the survival of the mice. At therapeutically achievable concentrations of PPP, the average survival was 180 days for the PPP-treated mice as compared to 100 days for vehicle-treated mice. PPP used as single drug treatment in the 5T2MM model resulted in a decrease of tumor burden by 65% while the paraprotein concentrations were reduced by 75%. This decrease was associated with a significant inhibition of tumor-associated angiogenesis and osteolysis. The present studies on the biological effects of PPP in the 5T2MM model constitute an important experimental platform for future therapeutic implementation.
authors.affiliation: Department of Hematology and Immunology, Vrije Universiteit Brussel-VUB, Brussels, Belgium. eline.menu@vub.ac.be
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.forename: Hendrik
authors.initials: H
authors.lastname: De Raeve
authors.forename: Evy
authors.initials: E
authors.lastname: De Leenheer
authors.forename: Les
authors.initials: L
authors.lastname: Coulton
authors.forename: Orla
authors.initials: O
authors.lastname: Gallagher
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Nilsson
authors.forename: Ben
authors.initials: B
authors.lastname: Van Camp
authors.forename: Peter
authors.initials: P
authors.lastname: Croucher
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000517:prevention & control*; D004195:Disease Models, Animal; D053208:Kaplan-Meier Estimate; D051379:Mice; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000187:drug effects*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin