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The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy.

ABSTRACT: Drug resistance remains an ongoing challenge for the majority of patients treated with inhibitors of the vascular endothelial growth factor (VEGF) pathway, a key regulator of tumor angiogenesis. Preclinical models have played a significant role in identifying multiple complex mechanisms of antiangiogenic treatment failure. Yet questions remain about the optimal methodology to study resistance that may assist in making clinically relevant choices about alternative or combination treatment strategies. The origins of antiangiogenic treatment failure may stem from the tumor vasculature, the tumor itself, or both together, and preclinical methods that define resistance are diverse and rarely compared. We performed a literature search of the preclinical methodologies used to examine resistance to VEGF pathway inhibitors and identified 109 papers from more than 400 that use treatment failure as the starting point for mechanistic study. We found that definitions of resistance are broad and inconsistent, involve only a small number of reagents, and derive mostly from in vitro and in vivo methodologies that often do not represent clinically relevant disease stages or progression. Together, this literature analysis highlights the challenges of studying inhibitors of the tumor microenvironment in the preclinical setting and the need for improved methodology to assist in qualifying (and quantifying) treatment failure to identify mechanisms that will help predict alternative strategies in patients.

SUBMITTER: Mastri M

PROVIDER: S-EPMC5673093 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy.

Mastri Michalis M Rosario Spencer S Tracz Amanda A Frink Robin E RE Brekken Rolf A RA Ebos John M L JM

Current drug targets 20160101 15

Drug resistance remains an ongoing challenge for the majority of patients treated with inhibitors of the vascular endothelial growth factor (VEGF) pathway, a key regulator of tumor angiogenesis. Preclinical models have played a significant role in identifying multiple complex mechanisms of antiangiogenic treatment failure. Yet questions remain about the optimal methodology to study resistance that may assist in making clinically relevant choices about alternative or combination treatment strateg ...[more]

PMID: 26648063

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Project description:Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.

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The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy.

Publications

The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy.

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