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.
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.
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Eline
E
Department of Hematology and Immunology, Vrije Universiteit Brussel-VUB, Brussels, Belgium. eline.menu@vub.ac.be
Jernberg-Wiklund
Helena
H
De Raeve
Hendrik
H
De Leenheer
Evy
E
Coulton
Les
L
Gallagher
Orla
O
Van Valckenborgh
Els
E
Larsson
Olle
O
Axelson
Magnus
M
Nilsson
Kenneth
K
Van Camp
Ben
B
Croucher
Peter
P
Vanderkerken
Karin
K
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*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin