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Leveraging Next Generation Sequencing to Elucidate the Spectrum of Genetic Alterations Underlying Head and Neck Cancer and Identify Potential Therapeutic Targets

Hedberg, Matthew (2015) Leveraging Next Generation Sequencing to Elucidate the Spectrum of Genetic Alterations Underlying Head and Neck Cancer and Identify Potential Therapeutic Targets. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Head and neck squamous cell carcinoma (HNSCC), is a cancer of the upper aerodigestive tract epithelium. Risk factors for HNSCC are smoking, alcohol use, and infection with oncogenic human papillomavirus (HPV). HPV(+)HNSCC has a better prognosis than HPV(-)HNSCC in the absence of smoking. Multimodal therapy, combining surgery, radiation therapy, and chemotherapy, is the standard of care for HPV(+) and HPV(-) HNSCC. Despite improvements in care, all stage survival rates for HNSCC (~60% and ~50%, at 5 and 10 years respectively), have only modestly improved in the last 3 decades.

Cetuximab, an antibody against the epidermal growth factor receptor (EGFR), and only FDA-approved targeted therapy in HNSCC, is efficacious in only a subset of patients, and no known biomarkers can identify which patients will respond. Traditionally, a lack of knowledge regarding the genetic alterations underlying HNSCC has stymied the development of additional targeted agents. We conducted whole exome sequencing (WES) studies that reveal a compendium of genetic alterations observed in primary, metastatic, and recurrent HNSCC. Which, together with functional analyses in preclinical models, have identified new potential therapeutic targets in HNSCC.
WES of 151 HNSCC tumors identified the phosphoinositol-3-kinase (PI3K) pathway and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) as the most commonly mutated oncogenic pathway and oncogene in HNSCC. PIK3CA alterations were found to promote growth, survival, and invasion in engineered HNSCC cell lines. PI3K inhibitors were effective in preclinical models of HNSCC, especially in those harboring endogenous PIK3CA mutations.

WES of patient-matched tumor pairs from 23 patients with metastatic or recurrent disease reveals a spectrum of inter-tumor genetic heterogeneity. Genetically, paired primary tumors are more similar to synchronous lymph node metastases than metachronous recurrent tumors. Newly acquired mutations in the discoidin domain receptor 2 (DDR2) gene were found in a subset of recurrent tumors. Mutations in this gene have been found to confer sensitivity to Src family kinase (SFK) inhibitors in other malignancies, and we found HNSCC cell lines with endogenous or engineered DDR2 mutations to be sensitive to dasatinib. These studies shed light on the underlying pathophysiology of HNSCC, and identify potential therapeutic targets for further investigation.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hedberg, Matthewmlh110@pitt.eduMLH110
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGrandis, Jennifer R.jgrandis@pitt.eduJGRANDIS
Committee ChairDeFranco, Donald B.dod1@pitt.eduDOD1
Committee MemberLee, Adrian V.avl10@pitt.eduAVL10
Committee MemberVan Houten, Bennettvanhoutenb@upmc.eduBEV15
Committee MemberNikiforov, Yuri E.yen1@pitt.eduYEN1
Date: 12 August 2015
Date Type: Publication
Defense Date: 27 July 2015
Approval Date: 12 August 2015
Submission Date: 7 August 2015
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 137
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: Head and Neck Cancer Whole Exome Sequencing PIK3CA Synchronous metastasis Metachronous recurrence Targeted therapy
Date Deposited: 12 Aug 2015 13:10
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/25920

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