ONCOGENIC PROPERTIES AND TARGETING OF NTRK1 IN BREAST CANCER

Simple item page
dc.contributor.advisorShih, Ie-Ming
dc.contributor.committeeMemberPark, Ben H.
dc.contributor.committeeMemberWang, Tian-Li
dc.creatorKyker-Snowman, Kelly
dc.creator.orcid0000-0003-2057-8136
dc.date.accessioned2018-10-03T02:07:01Z
dc.date.available2018-10-03T02:07:01Z
dc.date.created2018-05
dc.date.issued2018-03-23
dc.date.submittedMay 2018
dc.date.updated2018-10-03T02:07:02Z
dc.description.abstractTriple negative breast cancers (TNBC) comprise a highly aggressive cancer subtype with high mortality rates, high frequency of metastatic disease and a lack of targeted therapies. A fraction of these cancers also demonstrate amplification of the NTRK1 gene. The protein product of the NTRK1 gene, TrkA, is a receptor tyrosine kinase (RTK) that recognizes neuronal growth factor (NGF) leading to downstream signaling through MAPK and other pathways that promote survival and proliferation. Pan-Trk inhibitors have been developed against rare cancers with NTRK translocations that result in constitutive Trk kinase activity. Expansion of these inhibitors’ application to amplifications, particularly in TNBC, offers the potential for targeted therapies. Here, we engineered non-tumorigenic immortalized human mammary epithelial cell lines and human breast cancer cell lines to overexpress TrkA. Overexpressing clones demonstrated cancerous and pro-metastatic phenotypes, which were reversed upon exposure to the Trk inhibitor larotrectinib. In vitro, the MCF10A and hTERT-IMEC engineered cell lines showed growth factor independence, increased downstream proliferative and pro-survival signaling, alterations in three-dimensional culture, and migratory phenotypes in increased wound healing and microchannel migration. In vivo, TrkA-overexpressing MCF7 cells showed increased tumor growth and acquired the capacity to establish disseminated disease. Our results demonstrate the potential clinical utility of larotrectinib for targeting NTRK1 amplified breast cancers and inhibiting metastasis.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/59180
dc.language.isoen_US
dc.publisherJohns Hopkins University
dc.publisher.countryUSA
dc.subjectbreast cancer
dc.subjectTrkA
dc.subjectNTRK1
dc.subjectpersonalized medicine
dc.subjectlarotrectinib
dc.subjectRTK
dc.subjectTriple negative breast cancer
dc.subjectTNBC
dc.subjectMCF10A
dc.subjectMCF7
dc.subjecthTERT-IMEC
dc.subjectmetastatic
dc.subjectmetastasis
dc.subjectNGF
dc.titleONCOGENIC PROPERTIES AND TARGETING OF NTRK1 IN BREAST CANCER
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentCellular and Molecular Medicine
thesis.degree.disciplineCellular & Molecular Medicine
thesis.degree.grantorJohns Hopkins University
thesis.degree.grantorSchool of Medicine
thesis.degree.levelDoctoral
thesis.degree.namePh.D.
Files
Original bundle
Now showing 1 - 4 of 4
Thumbnail Image
Name:
KYKER-SNOWMAN-DISSERTATION-2018.pdf
Size:
4.28 MB
Format:
Adobe Portable Document Format
Download
No Thumbnail Available
Name:
Kyker-Snowman Thesis_2.docx
Size:
17.23 MB
Format:
Microsoft Word XML
Download
No Thumbnail Available
Name:
Kyker-Snowman Thesis_1.docx
Size:
17.23 MB
Format:
Microsoft Word XML
Download
No Thumbnail Available
Name:
Kyker-Snowman Thesis.docx
Size:
17.23 MB
Format:
Microsoft Word XML
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
LICENSE.txt
Size:
2.68 KB
Format:
Plain Text
Description:
Download
Collections
ETD -- Doctoral Dissertations