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PTPRT/D MUTATION OR PROMOTER METHYLATION: IMPLICATIONS FOR STAT3 INHIBITION

Peyser, Noah D (2015) PTPRT/D MUTATION OR PROMOTER METHYLATION: IMPLICATIONS FOR STAT3 INHIBITION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is a morbid and frequently fatal malignancy arising from the squamous epithelium of the upper aerodigestive tract. Survival rates have remained low and stagnant in recent decades even as our understanding of this disease has led to new treatment approaches, most notably the approval in 2006 of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor. The paucity of broadly effective targeted therapies for HNSCC patients illustrates the need for new targets for pharmacologic inhibition and biomarkers for predicting exquisite response to such agents. STAT3 is a potent oncogene that is hyperactivated by constitutive tyrosine phosphorylation in nearly all HNSCCs, where STAT3 represents a rational target for inhibition. As it is increasingly clear that most targeted therapies are unlikely to be broadly effective in unselected groups of patients, we have sought to identify genetic/epigenetic alterations of phosphatases that normally downregulate STAT3 in order to assess the potential utility of these alterations as predictive biomarkers for STAT3-targeted therapeutics. Our findings reveal that somatic mutation or promoter hypermethylation of PTPRT or PTPRD leads to loss of function of these phosphatases in HNSCC, concomitant with increased activation of STAT3 in preclinical models and tumor specimens. Importantly, these events are also associated with increased sensitivity to inhibitors of the STAT3 pathway in preclinical models. Together, these studies indicate that genetic or epigenetic alterations leading to loss of function of phosphatases that target STAT3 may ultimately serve as biomarkers for the selection of patients who will be most likely to respond to STAT3 inhibitors that are currently in preclinical and clinical development.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Peyser, Noah Dnop4@pitt.eduNOP4
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairJohnson, Daniel Ejohnsond@pitt.eduJOHNSOND
Committee MemberSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Committee MemberSorkin, Alexandersorkin@pitt.eduSORKIN
Committee MemberOesterreich, Steffisto16@pitt.eduSTO16
Thesis AdvisorGrandis, Jennifer Rjennifer.grandis@ucsf.edu
Date: 18 June 2015
Date Type: Publication
Defense Date: 5 June 2015
Approval Date: 18 June 2015
Submission Date: 15 June 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 97
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: head and neck cancer, phosphatase, mutation, methylation, biomarker
Date Deposited: 18 Jun 2015 15:50
Last Modified: 15 Nov 2016 14:28
URI: http://d-scholarship.pitt.edu/id/eprint/25421

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