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Pharmacology & Therapeutics Feb 2018Bevacizumab is a vascular endothelial growth factor-A-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of... (Review)
Review
Bevacizumab is a vascular endothelial growth factor-A-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of cancer. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy and lead to other cardiovascular complications. The factors that contribute to interindividual variability in blood pressure response to bevacizumab treatment are not well understood. In this review, we outline research efforts to understand the mechanisms and pathophysiology of hypertension resulting from bevacizumab treatment. Moreover, we highlight current knowledge of the pharmacogenetics of bevacizumab-induced hypertension, which may be used to develop strategies to prevent or minimize this toxicity.
Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal, Humanized; Bevacizumab; Humans; Hypertension; Models, Cardiovascular; Vasodilation
PubMed: 28882537
DOI: 10.1016/j.pharmthera.2017.08.012 -
Journal of Thoracic Oncology : Official... Nov 2021We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median...
INTRODUCTION
We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143).
METHODS
In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays.
RESULTS
At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71-1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018).
CONCLUSIONS
At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Humans; Lung Neoplasms; Paclitaxel; Survival Analysis
PubMed: 34311108
DOI: 10.1016/j.jtho.2021.07.009 -
Asia-Pacific Journal of Ophthalmology...Retinal vein occlusion represents the second leading cause of retinal vascular disorders, with a uniform sex distribution worldwide. A thorough evaluation of... (Review)
Review
Retinal vein occlusion represents the second leading cause of retinal vascular disorders, with a uniform sex distribution worldwide. A thorough evaluation of cardiovascular risk factors is required to correct possible comorbidities. The diagnosis and management of retinal vein occlusion have changed tremendously in the last 30 years, but the assessment of retinal ischemia at baseline and during follow-up examinations remains crucial. New imaging techniques have shed light on the pathophysiology of the disease and laser treatment, once the only therapeutic option, is now only one of the possible approaches with antivascular endothelial growth factors and steroid injections being preferred in most cases. Nowadays long-term outcomes are better than those achievable 20 years ago and yet, many new therapeutic options are under development, including new intravitreal drugs and gene therapy. Despite this, some cases still develop sight-threatening complications deserving a more aggressive (sometimes surgical) approach. The purpose of this comprehensive review is to reappraise some old but still valid concepts and to integrate them with new research and clinical data. The work will provide an overview of the disease's pathophysiology, natural history, and clinical features along with a detailed discussion on the advantages of multimodal imaging and of the different treatment strategies with the aim of providing retina specialists with the most updated knowledge in the field.
Topics: Humans; Retinal Vein Occlusion; Angiogenesis Inhibitors; Retina; Intravitreal Injections; Bevacizumab
PubMed: 36912792
DOI: 10.1097/APO.0000000000000598 -
Autophagy Jan 2024Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it...
Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation. 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.
Topics: Humans; Autophagy; Beclin-1; Bevacizumab; Colorectal Neoplasms; Epigenesis, Genetic; Histones; Hypoxia; Lactic Acid; Lysine
PubMed: 37615625
DOI: 10.1080/15548627.2023.2249762 -
Cancer Treatment Reviews Jun 2020When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and... (Review)
Review
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Bevacizumab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic
PubMed: 32335505
DOI: 10.1016/j.ctrv.2020.102017 -
The Indian Journal of Medical Research Aug 2021Cervical cancer is one of the most common cancers in the world both in terms of incidence and mortality, more so important in low- and middle-income countries. Surgery... (Review)
Review
Cervical cancer is one of the most common cancers in the world both in terms of incidence and mortality, more so important in low- and middle-income countries. Surgery and radiotherapy remain the backbone of treatment for non-metastatic cervical cancer, with significant improvement in survival provided by addition of chemotherapy to radiotherapy. Survival as well as quality of life is improved by chemotherapy in metastatic disease. Platinum-based chemotherapy with/without bevacizumab is the mainstay of treatment for metastatic disease and has shown improvement in survival. The right combinations and sequence of treatment modalities and medicines are still evolving. Data regarding the molecular and genomic biology of cervical cancer have revealed multiple potential targets for treatment, and several new agents are presently under evaluation including targeted therapies, immunotherapies and vaccines. This review discusses briefly the current standards, newer updates as well as future prospective approaches in systemic therapies for cervical cancer.
Topics: Bevacizumab; Female; Humans; Immunotherapy; Quality of Life; Uterine Cervical Neoplasms
PubMed: 35295013
DOI: 10.4103/ijmr.IJMR_4454_20 -
Nature Communications Apr 2023Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug...
Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility.
Topics: Humans; Vascular Endothelial Growth Factor A; Bevacizumab; Antibodies, Monoclonal; Neoplasms; Angiogenesis Inhibitors; Apoptosis Regulatory Proteins; Receptors, Scavenger
PubMed: 37100807
DOI: 10.1038/s41467-023-36910-5 -
Cancer Research Nov 2023Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a...
UNLABELLED
Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying a mechanism of antiangiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and posttreatment samples of liver metastases from 20 colorectal cancer patients treated with combination bevacizumab therapy, including 10 responders and 10 nonresponders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in nonresponders after antiangiogenic therapy compared with responders. In mouse models of liver metastatic colorectal cancer (mCRC), anti-VEGF increased ECM deposition and FAO in colorectal cancer cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSC) were essential for matrix stiffness-mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic cross-talk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance.
SIGNIFICANCE
Extracellular matrix stiffening drives bevacizumab resistance by stimulating hepatic stellate cells to provide fuel for mCRC cells in the liver, indicating a potential metabolism-based therapeutic strategy for overcoming resistance.
Topics: Animals; Mice; Humans; Bevacizumab; Liver Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Stromal Cells; Lipids; Tumor Microenvironment
PubMed: 37610655
DOI: 10.1158/0008-5472.CAN-23-0025 -
JAMA Network Open Aug 2023Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown.
IMPORTANCE
Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown.
OBJECTIVE
To investigate time-dependent changes in the outcomes of bevacizumab therapy.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed.
EXPOSURES
Bevacizumab treatment vs placebo or no treatment.
MAIN OUTCOMES AND MEASURES
Restricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups.
RESULTS
In the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P < .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P < .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P < .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P < .001; after, 0.71; 95% CI, 0.56-0.90; P < .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P < .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image-based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination-associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression.
CONCLUSIONS AND RELEVANCE
In ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome.
Topics: Humans; Female; Bevacizumab; Cohort Studies; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Ovarian Neoplasms
PubMed: 37531111
DOI: 10.1001/jamanetworkopen.2023.26834 -
Nature Communications Nov 2023Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients...
Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8 exhausted-like T cells.
Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8 T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8 T cells (CD8 Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8 Tpex, the progenitor exhausted CD8 T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation.
Topics: Humans; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Liver Neoplasms; Bevacizumab; Cell Line, Tumor; Vascular Endothelial Growth Factor A
PubMed: 38001101
DOI: 10.1038/s41467-023-43462-1