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dc.contributor.authorWajapeyee, Narendra
dc.contributor.authorKapoor, Varun
dc.contributor.authorMahalingam, Meera
dc.contributor.authorGreen, Michael R.
dc.date2022-08-11T08:10:16.000
dc.date.accessioned2022-08-23T17:01:50Z
dc.date.available2022-08-23T17:01:50Z
dc.date.issued2009-10-29
dc.date.submitted2011-04-19
dc.identifier.citationMol Cancer Ther. 2009 Nov;8(11):3009-14. Epub 2009 Oct 27. <a href="http://dx.doi.org/10.1158/1535-7163.MCT-09-0470">Link to article on publisher's site</a>
dc.identifier.issn1535-7163 (Linking)
dc.identifier.doi10.1158/1535-7163.MCT-09-0470
dc.identifier.pmid19861408
dc.identifier.urihttp://hdl.handle.net/20.500.14038/44092
dc.description.abstractWe 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=19861408&dopt=Abstract">Link to Article in PubMed</a>
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectCell Growth Processes
dc.subjectCell Line, Tumor
dc.subjectColorectal Neoplasms
dc.subjectEpigenesis, Genetic
dc.subjectGene Silencing
dc.subjectHT29 Cells
dc.subjectHumans
dc.subjectInsulin-Like Growth Factor Binding Proteins
dc.subjectMelanoma
dc.subjectMice
dc.subjectMice, Inbred BALB C
dc.subjectMice, Nude
dc.subjectProto-Oncogene Proteins B-raf
dc.subjectRecombinant Proteins
dc.subjectSignal Transduction
dc.subjectSurvival Rate
dc.subjectXenograft Model Antitumor Assays
dc.subjectras Proteins
dc.subjectGenetics and Genomics
dc.titleEfficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines
dc.typeJournal Article
dc.source.journaltitleMolecular cancer therapeutics
dc.source.volume8
dc.source.issue11
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1067&amp;context=pgfe_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/pgfe_pp/67
dc.identifier.contextkey1946721
refterms.dateFOA2022-08-23T17:01:50Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathpgfe_pp/67
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentProgram in Gene Function and Expression
dc.source.pages3009-14


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