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Identification of Acquired Molecular Dependencies in Advanced Breast and Ovarian Cancers

Priedigkeit, Nolan (2017) Identification of Acquired Molecular Dependencies in Advanced Breast and Ovarian Cancers. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Although individual cancers are driven by heterogeneous processes, cancer mortality has a near universal cause—therapy resistance, recurrence and eventual metastasis to vital organs. Despite great advancements in cancer therapies this past decade, outcomes in patients with advanced disease remain static. In these translational studies, using multiple cohorts of longitudinally collected tumor specimens, we test the hypothesis that relapsed cancers are molecularly distinct from primary disease and acquire druggable vulnerabilities throughout their life histories. As a preliminary study, a targeted gene expression analysis was performed to (1) determine differences in breast cancer (BrCa) intrinsic subtypes between primary tumors and matched brain metastases (BrM) and (2) explore if druggable targets are acquired in metastases. While BrM generally retain their intrinsic molecular subtypes, even after years of dormancy, nearly all gain expression of clinically actionable genes—most notably HER2 (35% of cases). To further assess molecular features acquired in metastases, exome-capture RNA-sequencing on decade-old and degraded tumor specimens was evaluated. Applying this technology, transcriptome-wide acquisitions in BrM were discovered, including highly recurrent expression gains in RET (38% of cases). Targeting RET or HER2 using in vitro, ex vivo, and in vivo models produced marked responses, suggesting RET and HER2-driven signaling as prime targets for patients with BrM. The same approach was applied to estrogen receptor [ER]-positive BrCa bone metastases, which discerned further site-specific acquisitions—such as shifts to Her2 and LumB phenotypes, temporally influenced expression evolution and druggable gains in CDK-Rb-E2F and FGFR-signaling pathways. To determine if these changes are consistent in non-metastatic samples, both RNA expression and DNA changes were assessed in a cohort of ER-positive local recurrences. Limited DNA-level changes, yet highly recurrent transcriptional remodeling events were observed—in particular, losses of ESR1, gains of NTRKs and upregulation of the cancer stem cell marker PROM1. Lastly, these findings were corroborated in ovarian cancer recurrences, where we show fusion RNA transcripts and recurrent outlier expression gains (NTRK2, INHBA and IGF1) are acquired in relapsed disease. Taken together, these studies establish that cancer recurrences commonly acquire multimodal and readily druggable molecular dependencies, unique from primary tumors, which may have profound clinical implications.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Priedigkeit, Nolannmp50@pitt.edunmp500000-0001-8330-5210
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorLee, Adrianleeav@upmc.eduavl10
Committee ChairSteinman, RichardSteinman@pitt.edusteinman
Committee MemberEdwards, Robertedwarp@mail.magee.edurpe1
Committee MemberOesterreich, Steffioesterreichs@upmc.edusto16
Committee MemberTseng, Georgectseng@pitt.eductseng
Date: 7 July 2017
Date Type: Publication
Defense Date: 19 June 2017
Approval Date: 7 July 2017
Submission Date: 23 June 2017
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 221
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Cancer, Breast Cancer, Ovarian Cancer, Genomics, RNA-sequencing, transcriptome, evolution, fusions, fusion genes, ESR1, cancer subtypes, HER2, RET
Date Deposited: 07 Jul 2017 14:41
Last Modified: 07 Jul 2017 14:41
URI: http://d-scholarship.pitt.edu/id/eprint/32521

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