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Characterizing Replication Stress in Glioblastoma

Rashid, Rumana (2025) Characterizing Replication Stress in Glioblastoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

This dissertation investigated glioblastoma multiforme (GBM), a highly aggressive brain malignancy with poor outcomes. The disease’s heterogeneity promotes treatment resistance and recurrence, with limited biomarkers available o guide therapy. MGMT promoter methylation, the sole clinical biomarker for temozolomide response, has limited predictive utility, underscoring the need for novel approaches.
This dissertation examined replication stress (RS), a key feature of GBM linked to DNA damage and genetic instability. Using advanced tissued-based multiplexed imaging technologies, RS was characterized at single-cell resolution in tumor specimens. High-dimensional biomarkers, including the Multidimensional Replication Stress Index (MRSI), were developed to quantify RS and identify therapeutic vulnerabilities.
The researched aimed to (1) identify and validate a panel of RS markers using multiplexed imaging, (2) develop the MRSI metric for quantifying RS data, (3) characterize RS profiles in primary GBM, and (4) assess RS modulation following drug treatment in a clinical trial for recurrent GBM. These efforts integrated imaging data with computational modeling to uncover novel biomarkers and stratify patients for personalized therapy.
This dissertation’s innovative use of multiplexed imaging enabled detailed visualization of protein dynamics and RS at multiple scales. Findings advanced biomarker development for GBM and provided a framework for addressing RS-driven vulnerabilities in other cancers, with potential implications for improving precision oncology.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Rashid, Rumanarur14@pitt.edurur140000-0001-6986-7209
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVisweswaran, Shyam
Committee MemberOsmanbeyoglu, Hatice
Thesis AdvisorBecich, Michael
Thesis AdvisorSantagata, Sandro
Date: 24 February 2025
Date Type: Publication
Defense Date: 4 December 2024
Approval Date: 24 February 2025
Submission Date: 19 December 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 119
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biomedical Informatics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: glioblastoma, biomarkers, single-cell, high-dimensional, imaging
Date Deposited: 24 Feb 2025 16:31
Last Modified: 24 Feb 2025 16:31
URI: http://d-scholarship.pitt.edu/id/eprint/47308

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