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.
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.
Mitsiades
Constantine S
CS
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. constantine_mitsiades@dfci.harvard.edu
Mitsiades
Nicholas S
NS
McMullan
Ciaran J
CJ
Poulaki
Vassiliki
V
Shringarpure
Reshma
R
Akiyama
Masaharu
M
Hideshima
Teru
T
Chauhan
Dharminder
D
Joseph
Marie
M
Libermann
Towia A
TA
García-Echeverría
Carlos
C
Pearson
Mark A
MA
Hofmann
Francesco
F
Anderson
Kenneth C
KC
Kung
Andrew L
AL
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
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