title: Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors.
abstract: Insulin-like growth factors and their receptor (IGF-1R) have been implicated in cancer pathophysiology. We demonstrate that IGF-1R is universally expressed in various hematologic (multiple myeloma, lymphoma, leukemia) and solid tumor (breast, prostate, lung, colon, thyroid, renal, adrenal cancer, retinoblastoma, and sarcoma) cells. Specific IGF-1R inhibition with neutralizing antibody, antagonistic peptide, or the selective kinase inhibitor NVP-ADW742 has in vitro activity against diverse tumor cell types (particularly multiple myeloma), even those resistant to conventional therapies, and triggers pleiotropic antiproliferative/proapoptotic molecular sequelae, delineated by global transcriptional and proteomic profiling. NVP-ADW742 monotherapy or its combination with cytotoxic chemotherapy had significant antitumor activity in an orthotopic xenograft MM model, providing in vivo proof of principle for therapeutic use of selective IGF-1R inhibitors in cancer.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. constantine_mitsiades@dfci.harvard.edu
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Mitsiades
authors.forename: Ciaran J
authors.initials: CJ
authors.lastname: McMullan
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Poulaki
authors.forename: Reshma
authors.initials: R
authors.lastname: Shringarpure
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akiyama
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Marie
authors.initials: M
authors.lastname: Joseph
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pearson
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
mesh_terms: D000970:Antineoplastic Agents; D001853:Bone Marrow / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009101:Multiple Myeloma; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014183:Transplantation, Heterologous / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C531185:ADW 742; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1