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Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.

ABSTRACT: VEGF-mediated tumor angiogenesis is a validated clinical target in many cancers, but modest efficacy and rapid development of resistance are major challenges of VEGF-targeted therapies. To establish a molecular signature of this resistance in ovarian cancer, we developed preclinical tumor models of adaptive resistance to chronic anti-VEGF treatment. We performed RNA-seq analysis and reverse-phase protein array to compare changes in gene and protein expressions in stroma and cancer cells from resistant and responsive tumors. We identified a unique set of stromal-specific genes that were strongly correlated with resistance phenotypes against two different anti-VEGF treatments, and selected the apelin/APJ signaling pathway for further in vitro validation. Using various functional assays, we showed that activation of apelin/APJ signaling reduces the efficacy of a VEGF inhibitor in endothelial cells. In patients with ovarian cancer treated with bevacizumab, increased expression of apelin was associated with significantly decreased disease-free survival. These findings link signature gene expressions with anti-VEGF response, and may thus provide novel targetable mechanisms of clinical resistance to anti-VEGF therapies.

SUBMITTER: Jaiprasart P

PROVIDER: S-EPMC6967771 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.

Jaiprasart Pharavee P Dogra Samrita S Neelakantan Deepika D Devapatla Bharat B Woo Sukyung S

Oncotarget 20200107 1

VEGF-mediated tumor angiogenesis is a validated clinical target in many cancers, but modest efficacy and rapid development of resistance are major challenges of VEGF-targeted therapies. To establish a molecular signature of this resistance in ovarian cancer, we developed preclinical tumor models of adaptive resistance to chronic anti-VEGF treatment. We performed RNA-seq analysis and reverse-phase protein array to compare changes in gene and protein expressions in stroma and cancer cells from res ...[more]

PMID: 32002127

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Project description:PURPOSE:To test the efficacy of the intravitreal dexamethasone (DEX) implant in patients with retinal vein occlusions (RVOs) who have failed multiple anti-vascular endothelial growth factor (anti-VEGF) treatments. METHODS:A randomized exploratory study of ten patients with branch RVO or central RVO who received at least two previous anti-VEGF treatments and had persistent or unresponsive cystoid macular edema. Treatment with the DEX implant was either every 4 months or pro re nata (PRN) depending on their group assignment for 1 year. Multifocal electroretinography and microperimetry were the primary end points, with high-resolution optical coherence tomography and best-corrected visual acuity as the secondary end points. RESULTS:All patients in both the every 4 month and PRN cohorts who completed the study received the three maximal injections of DEX; therefore, the data from both cohorts were combined and reported as a case series. On average, the multifocal electroretinography amplitude increased significantly from 5.11±0.66 to 24.19±5.30 nV/deg2 at 12 months (P<0.005), mean macular sensitivity increased from 7.67±2.10 to 8.01±1.98 dB at 4 months (P=0.32), best-corrected visual acuity increased significantly from 51.0±5.1 to 55.4±5.1 early treatment of diabetic retinopathy study letters at 2 months (P<0.05), and central retinal thickness decreased from 427.6±39.5 to 367.1±37.8 ?m at 4 months (P<0.05). Intraocular pressure increased significantly in one patient, with that patient requiring an additional glaucoma medication for management. Additionally, cataract progression increased significantly (P<0.05) in this patient population and partially limited analysis of other end points. CONCLUSION:DEX should be considered as a treatment option in patients with RVOs who have failed anti-VEGF therapy, as the results of this study demonstrated an improvement in retinal morphology and macular function. Cataract progression did occur following multiple consecutive injections; however, steroid-induced glaucoma was not a limiting factor.

Project description:Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.

Dataset Information

Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.

Publications

Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.

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