Characterizing the anti-angiogenic resistance potential of cross-family PDGF:VEGFR2 interactions in glioblastoma
Castleberry, Colin
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https://hdl.handle.net/2142/115508
Description
Title
Characterizing the anti-angiogenic resistance potential of cross-family PDGF:VEGFR2 interactions in glioblastoma
Author(s)
Castleberry, Colin
Issue Date
2022-03-24
Director of Research (if dissertation) or Advisor (if thesis)
Imoukhuede, Princess I
Amos, Jennifer
Doctoral Committee Chair(s)
Jensen, Paul
Committee Member(s)
Dobrucki, Wawrzyniec
Chen, Jie
Department of Study
Bioengineering
Discipline
Bioengineering
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
VEGF
PDGF
cross-family signaling
RTK
cell signaling
cancer
angiogenesis
computational modeling
mass action kinetics
global sensitivity analysis
structural alignment
meta-analysis
glioblastoma
growth factors
Abstract
Glioblastoma is the most common and lethal primary brain tumor in adults. Anti-angiogenic treatment has shown positive results in improving GBM patient survival. Bevacizumab, a drug that sequesters the angiogenic growth factor, VEGF-A, has been approved by the FDA for use in GBM patients and moderately improves patient survival; however, these GBM bevacizumab responders eventually acquire bevacizumab resistance. New approaches must be pursued to understand anti-VEGF resistance in GBM. The involvement of other signaling axes potentially explains anti-VEGF failings. PDGF:VEGFR2 interactions were recently discovered and prior computational modeling predicts that PDGF:VEGFR2 interactions could constitute a large proportion of VEGFR2-ligand complexes in certain physiological and breast cancer conditions. Under PDGF:VEGFR2 cross-family signaling, upregulated PDGFs would directly activate VEGFRs and lead to anti-VEGF therapy resistance. We aimed to use computational tools to assess how strongly PDGFs can affect VEGFR occupancy in GBM, and to assess the potential of PDGF:VEGFR2 interactions as resistance mechanisms for anti-VEGF treatment in GBM. However, the GBM ligand and receptor parameter space has not been established such that a GBM condition can be computationally modelled, and an analysis platform has not yet been developed to assess the ability of cross-family PDGF ligands to control VEGFR-occupancy in relation to canonical VEGF-family ligands in pathology.
These challenges have been addressed in two ways: (1) I created and analyze a toolbox of computational models to compare PDGF:VEGFR2 interactions with canonical VEGF:VEGFR interactions across several mechanistic differences and assumptions in angiogenic signaling, and (2) I performed an in-depth meta-analysis of GBM growth factors, including: VEGF-A, Ang-2, PDGF-BB, FGF-2, EGF, PlGF, and IGF in order to better characterize the GBM growth factor landscape, and to consolidate concentration data for the ligands aiding tumor growth and angiogenesis.
Graduation Semester
2022-05
Type of Resource
Thesis
Copyright and License Information
Copyright by Colin Castleberry 2022. All Rights Reserved.
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