Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines.
We recently identified the secreted protein IGFBP7 as a factor required for an activated BRAF oncogene to induce senescence or apoptosis in primary human cells. In human melanomas containing an activating BRAF mutation (BRAF-positive melanomas), IGFBP7 is epigenetically silenced, which seems to be a critical step in melanoma genesis. Restoration of IGFBP7 function by the addition of recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAF-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses the growth of BRAF-positive primary tumors in xenografted mice. Here we further evaluate the role of IGFBP7 in the treatment of BRAF-positive melanoma and other malignancies. We find that in human metastatic melanoma samples IGFBP7 is epigenetically silenced and at an even higher frequency than that found in primary melanomas. Using a murine experimental metastasis assay, we show that systemic administration of rIGFBP7 markedly suppresses the growth of metastatic disease and prolongs survival. An analysis of the NCI60 panel of human cancer cell lines reveals that in addition to melanoma, IGFBP7 induces apoptosis in several other cancer types, in particular colorectal cancer cell lines. In general, IGFBP7 induces apoptosis in human cancer cell lines that have an activating mutation in BRAF or RAS, and that are sensitive to chemical inhibition of BRAF-MEK-ERK signaling. Significantly, systemically administered rIGFBP7 blocks the growth of colorectal tumors containing an activating RAS or BRAF mutation in mouse xenografts. The results presented here, in conjunction with those from previous studies, justify the further development of IGFBP7 as an anticancer agent.
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Narendra
N
Wajapeyee
Varun
V
Kapoor
Meera
M
Mahalingam
Michael R
MR
Green
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D019073:HT29 Cells; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048493:Proto-Oncogene Proteins B-raf / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
D018969:Insulin-Like Growth Factor Binding Proteins; D011994:Recombinant Proteins; C102529:insulin-like growth factor binding protein-related protein 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins