RESUMO
PURPOSE: To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS: Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS: Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). CONCLUSIONS: Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Glucocorticoides/uso terapêutico , Edema Macular/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Academias e Institutos/normas , Bevacizumab/uso terapêutico , Bases de Dados Factuais , Dexametasona/uso terapêutico , Retinopatia Diabética/fisiopatologia , Tratamento Farmacológico , Humanos , Injeções Intravítreas , Edema Macular/fisiopatologia , Oftalmologia/organização & administração , Ranibizumab/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Avaliação da Tecnologia Biomédica , Resultado do Tratamento , Estados Unidos , Acuidade Visual/fisiologiaRESUMO
Tumor growth and progression are critically dependent on the establishment of a vascular support system. This is often accomplished via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. VEGF ligands are overexpressed in a wide variety of solid tumors and therefore have inspired optimism that inhibition of the different axes of the VEGF pathway-alone or in combination-would represent powerful anti-angiogenic therapies for most cancer types. When considering treatments that target VEGF and its receptors, it is difficult to tease out the differential anti-angiogenic and anti-tumor effects of all combinations experimentally because tumor cells and vascular endothelial cells are engaged in a dynamic cross-talk that impacts key aspects of tumorigenesis, independent of angiogenesis. Here we develop a mathematical model that connects intracellular signaling responsible for both endothelial and tumor cell proliferation and death to population-level cancer growth and angiogenesis. We use this model to investigate the effect of bidirectional communication between endothelial cells and tumor cells on treatments targeting VEGF and its receptors both in vitro and in vivo. Our results underscore the fact that in vitro therapeutic outcomes do not always translate to the in vivo situation. For example, our model predicts that certain therapeutic combinations result in antagonism in vivo that is not observed in vitro. Mathematical modeling in this direction can shed light on the mechanisms behind experimental observations that manipulating VEGF and its receptors is successful in some cases but disappointing in others.
Assuntos
Modelos Biológicos , Neoplasias/terapia , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Animais , Comunicação Celular , Proliferação de Células , Técnicas de Cocultura , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Humanos , Conceitos Matemáticos , Neoplasias/patologia , Neoplasias/fisiopatologia , Neovascularização Patológica , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Transdução de Sinais , Fatores de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological syndrome characterized by acute hypertension, headache, decreased level of consciousness, visual disturbances and seizures associated with characteristic neuroimaging changes indicative of vasogenic edema of the posterior cerebral white matter. Several medical conditions have been associated with PRES including hypertensive encephalopathy and eclampsia. The use of cytotoxic and immunosuppressant drugs, such as those which target vascular endothelial growth factor (VEGF), have also been implicated. We report here the case of a 71-year-old woman with metastatic clear cell renal carcinoma who developed PRES 3 months after commencing sorafenib. Elevated blood pressure (BP) was recorded, and MRI of the brain) of the brain showed asymmetric areas of increased signal intensity within the supratentorial white matter suggestive of PRES. Clinical and radiological features rapidly improved with BP control and discontinuation of sorafenib. Sorafenib was resumed with no sign of PRES recurrence. The present case report supports the hypothesis that, in selected patients, the re-introduction of anti-VEGF therapies after PRES is feasible.
Assuntos
Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/tratamento farmacológico , Imunossupressores/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Renais/tratamento farmacológico , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Sorafenibe/efeitos adversos , Idoso , Pressão Sanguínea , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Hipertensão/patologia , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Metástase Neoplásica , Recidiva Local de Neoplasia , Sorafenibe/uso terapêutico , Trombose/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Angiogenesis is a crucial process for tissue development, repair, and tumor survival. Vascular endothelial growth factor (VEGF) is a key driver secreted by cancer cells, promoting neovascularization. While VEGF's role in angiogenesis is well-documented, its influence on the other aspects in tumor microenvironemt is less discussed. This review elaborates on VEGF's impact on intercellular interactions within the tumor microenvironment, including how VEGF affects pericyte proliferation and migration and mediates interactions between tumor-associated macrophages and cancer cells, resulting in PDL-1-mediated immunosuppression and Nrf2-mediated epithelial-mesenchymal transition. The review discusses VEGF's involvement in intra-organelle crosstalk, tumor metabolism, stemness, and epithelial-mesenchymal transition. It also provides insights into current anti-VEGF therapies and their limitations in cancer treatment. Overall, this review aims to provide a thorough overview of the current state of knowledge concerning VEGF signaling and its impact, not only on angiogenesis but also on various other oncogenic processes.
Assuntos
Angiogênese , Transdução de Sinais , Fatores de Crescimento do Endotélio Vascular , Humanos , Neoplasias/patologia , Microambiente TumoralRESUMO
Despite extensive use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics for over a decade, neovascular age-related macular degeneration (nAMD) or choroidal neovascularization (CNV) continues to be a major cause of irreversible vision loss in developed countries. Many nAMD patients demonstrate persistent disease activity or experience declining responses over time despite anti-VEGF treatment. The underlying mechanisms of anti-VEGF resistance are poorly understood, and no effective treatment strategies are available to date. Here we review evidence from animal models and clinical studies that supports the roles of neovascular remodeling and arteriolar CNV formation in anti-VEGF resistance. Cholesterol dysregulation, inflammation, and ensuing macrophage activation are critically involved in arteriolar CNV formation and anti-VEGF resistance. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV.
Assuntos
Neovascularização de Coroide , Degeneração Macular , Animais , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Fator A de Crescimento do Endotélio Vascular , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Neovascularização de Coroide/tratamento farmacológico , Fatores de Crescimento do Endotélio Vascular , ColesterolRESUMO
Although anti-angiogenic agents targeting VEGF have shown affordable beneficial outcomes in several human cancer types, in most pre-clinical and clinical studies, these effects are transient and followed by rapid relapse and tumor regrowth. Recently, it has been suggested that recruited bone marrow derived cells (BMDCs) to the tumor-microenvironment together with stromal cells play an important role in development of resistance to anti-VEGF therapies. Additionally, acquired resistance to anti-VEGF therapies has shown to be mediated partly through overexpression of different pro-angiogenic cytokines and growth factors including G-CSF, IL-6, IL-8, VEGF and FGF by these cells. Alongside, IL-17, a pro-inflammatory cytokine, mostly secreted by infiltrated CD4+ T helper cells, has shown to mediate resistance to anti-VEGF therapies, through recruiting BMDCs and modulating stromal cells activities including endothelial cells, tumor associated macrophages and cancer associated fibroblasts. Here, we examined the role of BMDCs, tumor stromal cells, IL-17 and their negotiation in development of resistance to anti-VEGF targeted therapies.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Interleucina-17/imunologia , Neoplasias/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Citocinas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neoplasias/patologia , Células Estromais/efeitos dos fármacos , Células Estromais/imunologia , Células Estromais/patologia , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
Introduction The vascular endothelial growth factor A (VEGF) is the main mediator of angiogenesis. In addition, VEGF contributes to cancer growth and metastasis directly targeting tumor cells. VEGF overexpression and/or high VEGF serum levels have been reported in lung cancer. Areas covered We searched Pubmed for relevant preclinical studies with the terms 'lung cancer' 'VEGF' and 'in vivo'. We also searched the Clinicaltrials.gov database, the FDA and the EMA websites for the most recent updates on clinical development of anti-VEGF agents. Expert opinion VEGF plays an important role in sustaining the development and progression of lung cancer and it might represent an attractive target for therapeutic strategies. Nevertheless, clinical trials failed to attend the promising expectations deriving from preclinical studies with anti-VEGF agents. To improve the efficacy of anti-VEGF therapies in lung cancer, potential strategies might be the employment of combinatory therapies with immune checkpoint inhibitors or agents that inhibit signaling pathways and proangiogenic factors activated in response to VEGF blockade, and the identification of novel targets in the VEGF cascade. Finally, the identification of predictive markers might help to select patients who are more likely to respond to anti-angiogenic drugs.