RESUMEN
BACKGROUND: While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. OBJECTIVES: The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. PATIENTS AND METHODS: This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. CONCLUSION: Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Bevacizumab , Carcinoma Hepatocelular , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Masculino , Femenino , Bevacizumab/uso terapéutico , Bevacizumab/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Adulto , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologíaRESUMEN
ABSTRACT: Glioblastoma multiforme (GBM) is a highly vascularized tumor with reported high prostate-specific membrane antigen (PSMA) expression. On the other hand, bevacizumab as an antiangiogenesis drug is increasingly used in the treatment of GBM recurrence. We present a case of GBM recurrence with significant reduction of 99m Tc-HYNIC-PSMA-11 uptake in her tumor 1 week after administration of 2 doses of bevacizumab with 2 weeks' interval. This case emphasizes the main mechanism of PSMA uptake in GBM secondary to angiogenesis and also implies a potential interaction of bevacizumab with PSMA uptake that should be especially considered during diagnostic and therapeutic application of PSMA radiotracers in GBM.
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Bevacizumab , Glioblastoma , Compuestos de Organotecnecio , Humanos , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Femenino , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Recurrencia , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Transporte Biológico , Persona de Mediana Edad , Ácido Edético/análogos & derivados , Radioisótopos de Galio , Octreótido/análogos & derivadosRESUMEN
Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.
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Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Bevacizumab , Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Bevacizumab/uso terapéutico , Bevacizumab/farmacología , Masculino , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Persona de Mediana Edad , Anciano , Mesotelioma Maligno/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Mesotelioma/inmunología , Mesotelioma/tratamiento farmacológico , Mesotelioma/microbiología , Mesotelioma/patología , Microambiente Tumoral/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/microbiología , Resultado del TratamientoRESUMEN
Colorectal cancer (CRC), as a fatal cancer, is one of the most common cancers worldwide. Although the standard treatment for colorectal cancer is well researched and established, long-term patient survival remains poor, and mortality remains high. Therefore, more and more effective treatment options are needed. To evaluate the efficacy of bevacizumab, the histone demethylase inhibitor IOX1, or their combination for the treatment of colorectal cancer, we examined the effects of IOX1, bevacizumab, and IOX1 combined with bevacizumab on cell activity, proliferation, and migration of colorectal cancer cell lines HCT116, RKO, and CT26 by CCK8, colony formation assay, wound healing assay, and transwell assay. The effects of the drugs alone as well as in combination on apoptosis in colorectal cancer cell lines were examined by flow cytometry and further validated by Western blotting for apoptosis-related proteins. The antitumor effects of treatment alone or in combination on colorectal cancer cells were examined in animal models. Mice were injected subcutaneously with CT26 cells and the growth and immune infiltration in tumor tissues were detected by IHC after drug treatment. We found that IOX1 could effectively inhibit the activity of CRC cells and had a significant inhibitory effect on the proliferation and migration of CRC cells. The apoptosis rate increased in a dose-dependent manner after IOX1 treatment on colorectal cancer cells, and the expression of apoptosis-related proteins changed accordingly. Further combination with bevacizumab revealed that the combination had a more significant effect on the proliferation, migration, and apoptosis of CRC cells than either IOX1 or bevacizumab alone. In vivo experiments have found that both alone and combination drugs can inhibit the growth of mouse tumors, but the effect of combination inhibition is the most obvious. Combination therapy significantly inhibited the expression of proliferative marker (Ki67) in tumor xenograft models, and increased content of antigen-specific CD4+, CD8+T cell growth, and granzymeB (GZMB), which is associated with T cell cytotoxicity, was detected in combination therapy. Immunoassays suppressed the expression of relevant PD-1 and decreased. The anticancer drug bevacizumab and the histone demethylase inhibitor IOX1 may inhibit colon cancer cell growth by regulating apoptosis. The inhibitory effect of combination therapy on tumor growth may be achieved, in part, through upregulation of infiltration-mediated tumor immunity by T lymphocytes. The combination of IOX1 and bevacizumab produced significant synergistic effects. This study aims to provide a new direction for CRC combination therapy.
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Apoptosis , Bevacizumab , Proliferación Celular , Neoplasias Colorrectales , Animales , Bevacizumab/uso terapéutico , Bevacizumab/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Humanos , Apoptosis/efectos de los fármacos , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ratones Desnudos , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/metabolismoRESUMEN
Immunotherapies have significantly improved the prognosis of patients with advanced hepatocellular carcinoma (HCC), although more than 70% of patients still do not respond to this first-line treatment. Many new combination strategies are currently being explored, which drastically increases the need for preclinical models that would allow large-scale testing of new immunotherapies and their combinations. We developed several in ovo (in the egg) human liver cancer models, based on human tumor xenografts of different liver cancer cell lines on the chicken embryo's chorioallantoic membrane. We characterized the angiogenesis, as well as the collagen accumulation and tumor immune microenvironment, and tested atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF) treatment. Our results show the involvement of chicken immune cells in tumor growth, reproducing a classical non-inflamed "cold" as well as inflamed "hot" tumor status, depending on the in ovo liver cancer model. The treatment by atezolizumab and bevacizumab was highly efficient in the "hot" tumor model PLC/PRF/5 in ovo with the reduction of tumor size by 76% (p ≤ .0001) compared with the control, whereas the efficacy was limited in the "cold" Hep3B in ovo tumor. The contribution of the anti-PD-L1 blockade to the anti-tumoral effect in the PLC/PRF/5 in ovo model was demonstrated by the efficacy of atezolizumab monotherapy (p = .0080, compared with the control). To conclude, our study provides a detailed characterization and rational arguments that could help to partially replace conventional laboratory animals with a more ethical model, suited to the current needs of preclinical research of new immunotherapies for liver cancer.
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Anticuerpos Monoclonales Humanizados , Bevacizumab , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/inmunología , Embrión de Pollo , Bevacizumab/uso terapéutico , Bevacizumab/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/inmunología , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Microambiente Tumoral/efectos de los fármacos , Inmunoterapia/métodos , Membrana Corioalantoides/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
The direct antitumor effect of bevacizumab (BEV) has long been debated. Evidence of the direct antitumor activities of drugs are mainly obtained from in vitro experiments, which are greatly affected by experimental conditions. In this study, we evaluated the effect of BEV-containing medium renewal on the results of in vitro cytotoxicity experiments in A549 and U251 cancer cells. We observed starkly different results between the experiments with and without BEV-containing medium renewal. Specifically, BEV inhibited the tumor cell growth in the timely replacement with a BEV-containing medium but promoted tumor cell growth without medium renewal. Meanwhile, compared with the control, a significant basic fibroblast growth factor (bFGF) accumulation in the supernatant was observed in the group without medium renewal but none in that with replaced medium. Furthermore, bFGF neutralization partially reversed the pro-proliferative effect of BEV in the medium non-renewed group, while exogenous bFGF attenuated the tumor cell growth inhibition of BEV in the medium-renewed group. Our data explain the controversy over the direct antitumor effect of BEV in different studies from the perspective of the compensatory autocrine cytokines in tumor cells.
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Bevacizumab , Proliferación Celular , Factor 2 de Crecimiento de Fibroblastos , Humanos , Factor 2 de Crecimiento de Fibroblastos/farmacología , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Bevacizumab/farmacología , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Medios de Cultivo/química , Medios de Cultivo/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/farmacología , Células A549 , Antineoplásicos Inmunológicos/farmacologíaRESUMEN
In the randomized, double-blind, multicenter study by Wang et al.,1 the addition of serplulimab (a PD-1 antibody) to anti-VEGF (HLX04; a bevacizumab biosimilar) together with chemotherapy (XELOX) was deemed to be tolerable and safe and may improve progression-free survival. However, even if adverse events were comparable, oncological endpoints including survival need to be confirmed in the next phase 3 study.
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Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Neoplasias Colorrectales , Factor A de Crecimiento Endotelial Vascular , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Capecitabina/uso terapéutico , Capecitabina/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/inmunología , Oxaloacetatos , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Bevacizumab/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Supervivencia sin Progresión , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificaciónRESUMEN
As a kind of proteolytic enzyme extracted from earthworms, lumbrokinase has been used as an antithrombotic drug clinically. Nevertheless, its potential in anti-cancer, especially in anti-non-small cell lung cancer (NSCLC), as a single form of treatment or in combination with other therapies, is still poorly understood. In this study, we explored the anti-tumor role and the responsive molecular mechanisms of lumbrokinase in suppressing tumor angiogenesis and chemoresistance development in NSCLC and its clinical potential in combination with bevacizumab and chemotherapeutics. Lumbrokinase was found to inhibit cell proliferation in a concentration-dependent manner and caused metastasis suppression and apoptosis induction to varying degrees in NSCLC cells. Lumbrokinase enhanced the anti-angiogenesis efficiency of bevacizumab by down-regulating BPTF expression, decreasing its anchoring at the VEGF promoter region and subsequent VEGF expression and secretion. Furthermore, lumbrokinase treatment reduced IC50 values of chemotherapeutics and improved their cytotoxicity in parental and chemo-resistant NSCLC cells via inactivating the NF-κB pathway, inhibiting the expression of COX-2 and subsequent secretion of PGE2. LPS-induced NF-κB activation reversed its inhibition on NSCLC cell proliferation and its synergy with chemotherapeutic cytotoxicity, while COX-2 inhibitor celecoxib treatment boosted such effects. Lumbrokinase combined with bevacizumab, paclitaxel, or vincristine inhibited the xenograft growth of NSCLC cells in mice more significantly than a single treatment. In conclusion, lumbrokinase inhibited NSCLC survival and sensitized NSCLC cells to bevacizumab or chemotherapeutics treatment by targeted down-regulation of BPTF/VEGF signaling and inactivation of NF-κB/COX-2 signaling, respectively. The combinational applications of lumbrokinase with bevacizumab or chemotherapeutics are expected to be developed as promising candidate therapeutic strategies to improve the efficacy of the original monotherapy in anti-NSCLC.
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Bevacizumab , Carcinoma de Pulmón de Células no Pequeñas , Ciclooxigenasa 2 , Sinergismo Farmacológico , Neoplasias Pulmonares , FN-kappa B , Oligoquetos , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , FN-kappa B/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Transducción de Señal/efectos de los fármacos , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , EndopeptidasasRESUMEN
Glioblastoma poses significant challenges in oncology, with bevacizumab showing promise as an antiangiogenic treatment but with limited efficacy. microRNAs (miRNAs) 10b and 21 have emerged as potential biomarkers for bevacizumab response in glioblastoma patients. This study delves into the expression dynamics of miR-21 and miR-10b in response to hypoxia and explores their circulation mechanisms. In vitro experiments exposed glioma cells (A172, U87MG, U251) and human umbilical vein endothelial cells (HUVEC) to hypoxic conditions (1% oxygen) for 24 h, revealing heightened levels of miR-10b and miR-21 in glioblastoma cells. Manipulating miR-10b expression in U87MG, demonstrating a significant decrease in VEGF alpha (VEGFA) following miR-10b overexpression under hypoxic conditions. Size exclusion chromatography illustrated a notable shift towards miR-21 and miR-10b exosomal packaging during hypoxia. A proposed model suggests that effective bevacizumab treatment reduces VEGFA levels, heightening hypoxia and subsequently upregulating miR-21 and miR-10b expression. These miRNAs, released via exosomes, might impact various cellular processes, with miR-10b notably contributing to VEGFA level reduction. However, post-treatment increases in miR-10b and miR-21 could potentially restore cells to normoxic conditions through the downregulation of VEGF. This study highlights the intricate feedback loop involving miR-10b, miR-21, and VEGFA in glioblastoma treatment, underscoring the necessity for personalized therapeutic strategies. Further research should explore clinical implications for personalized glioma treatments.
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Regulación Neoplásica de la Expresión Génica , Glioblastoma , Células Endoteliales de la Vena Umbilical Humana , MicroARNs , Factor A de Crecimiento Endotelial Vascular , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Glioblastoma/metabolismo , Glioblastoma/genética , Glioblastoma/patología , Línea Celular Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Hipoxia de la Célula/genética , Bevacizumab/farmacología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Exosomas/metabolismo , Exosomas/genéticaRESUMEN
INTRODUCTION: Angiogenesis is critical for tumor growth and metastasis. Bevacizumab is an antiangiogenic drug used to treat various adult and childhood solid tumors. Its potential efficacy in Wilms tumor (WT) with poor prognosis is not established. AREAS COVERED: The response to bevacizumab-containing regimens in relapsed or refractory WT was reviewed in available literature. Searches were conducted using PubMed, Scopus, and ClinicalTrials.gov databases. Eight papers were identified, published between 2007 and 2020, including six treatment regimens, predominantly vincristine, irinotecan, and bevacizumab (VIB) ± temozolomide (VITB). Among 16 evaluable patients, there were two complete responses, seven partial responses, five patients achieved stable disease (SD), and two patients had progressive disease. Objective responses (OR) were observed in 56% of all cases. OR or SD was observed in 89% (8/9) patients who received VIB/VITB. Bevacizumab was generally well tolerated. Related toxicities included hypertension, proteinuria, and delayed wound healing. EXPERT OPINION: This review suggests potential effectiveness and good tolerability of bevacizumab in the setting of relapsed/refractory WT when used in combination with other drugs. Such combination therapies may serve as a bridging treatment option to other interventions and more personalized treatment options in the future; however, focused trials are needed to obtain additional evidence.
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Inhibidores de la Angiogénesis , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Renales , Recurrencia Local de Neoplasia , Tumor de Wilms , Humanos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Bevacizumab/farmacología , Tumor de Wilms/tratamiento farmacológico , Tumor de Wilms/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Niño , Pronóstico , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patologíaRESUMEN
BACKGROUND: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Camptotecina , Neoplasias Colorrectales , Fluorouracilo , Genotipo , Glucuronosiltransferasa , Leucovorina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Bevacizumab/administración & dosificación , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Bevacizumab/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Masculino , Femenino , Glucuronosiltransferasa/genética , Persona de Mediana Edad , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Leucovorina/efectos adversos , Anciano , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacología , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Adulto , Anciano de 80 o más Años , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Irinotecán/efectos adversos , Irinotecán/farmacologíaRESUMEN
The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.
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Barrera Hematoencefálica , Factor A de Crecimiento Endotelial Vascular , Humanos , Masculino , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Niño , Adrenoleucodistrofia/tratamiento farmacológico , Bevacizumab/uso terapéutico , Bevacizumab/farmacología , Preescolar , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacologíaRESUMEN
Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been widely used to treat the neovascular type of AMD (nAMD). However, VEGF acts not only as a pro-angiogenic factor but also as an anti-apoptotic factor in the eyes. In this study, we found that anti-VEGF drugs, including bevacizumab (Bev), ranibizumab (Ran), and aflibercept (Afl), induced epithelial-mesenchymal transition (EMT) in ARPE-19 cells in vitro, accompanied by the induction of CCN2, a potent pro-fibrotic factor. Similarly, intravitreal injection of Afl into mouse eyes resulted in EMT in the retinal pigmented epithelium (RPE). Co-treatment with CCN5, an anti-fibrotic factor that down-regulates CCN2 expression, significantly attenuated the adverse effects of the anti-VEGF drugs both in vitro and in vivo. Inhibition of the VEGF signaling pathway with antagonists of VEGF receptors, SU5416 and ZM323881, induced EMT and up-regulated CCN2 in ARPE-19 cells. Additionally, knock-down of CCN2 with siRNA abolished the adverse effects of the anti-VEGF drugs in ARPE-19 cells. Collectively, these results suggest that anti-VEGF drugs induce EMT in RPE through the induction of CCN2 and that co-treatment with CCN5 attenuates the adverse effects of anti-VEGF drugs in mouse eyes.
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Transición Epitelial-Mesenquimal , Epitelio Pigmentado de la Retina , Factor A de Crecimiento Endotelial Vascular , Transición Epitelial-Mesenquimal/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patología , Animales , Humanos , Ratones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Degeneración Macular/metabolismo , Degeneración Macular/patología , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/inducido químicamente , Línea Celular , Bevacizumab/farmacología , Proteínas CCN de Señalización Intercelular/metabolismo , Proteínas CCN de Señalización Intercelular/genética , Inhibidores de la Angiogénesis/farmacología , Ranibizumab/farmacología , Proteínas Recombinantes de Fusión/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas Represoras , Receptores de Factores de Crecimiento Endotelial VascularRESUMEN
Purpose: To compare gene expression changes following branch retinal vein occlusion (BRVO) in the pig with and without bevacizumab (BEV) and triamcinolone acetonide (TA). Methods: Photothrombotic BRVOs were created in both eyes of four groups of nine pigs (2, 6, 10, and 20 days). In each group, six pigs received intravitreal injections of BEV in one eye and TA in the fellow eye, with three pigs serving as untreated BRVO controls. Three untreated pigs served as healthy controls. Expression of mRNA of vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), dystrophin (DMD), potassium inwardly rectifying channel subfamily J member 10 protein (Kir4.1, KCNJ10), aquaporin-4 (AQP4), stromal cell-derived factor-1α (CXCL12), interleukin-6 (IL6), interleukin-8 (IL8), monocyte chemoattractant protein-1 (CCL2), intercellular adhesion molecule 1 (ICAM1), and heat shock factor 1 (HSF1) were analyzed by quantitative reverse-transcription polymerase chain reaction. Retinal VEGF protein levels were characterized by immunohistochemistry. Results: In untreated eyes, BRVO significantly increased expression of GFAP, IL8, CCL2, ICAM1, HSF1, and AQP4. Expression of VEGF, KCNJ10, and CXCL12 was significantly reduced by 6 days post-BRVO, with expression recovering to healthy control levels by day 20. Treatment with BEV or TA significantly increased VEGF, DMD, and IL6 expression compared with untreated BRVO eyes and suppressed BRVO-induced CCL2 and AQP4 upregulation, as well as recovery of KCNJ10 expression, at 10 to 20 days post-BRVO. Conclusions: Inflammation and cellular osmohomeostasis rather than VEGF suppression appear to play important roles in BRVO-induced retinal neurodegeneration, enhanced in both BEV- and TA-treated retinas. Translational Relevance: Inner retinal neurodegeneration seen in this acute model of BRVO appears to be mediated by inflammation and alterations in osmohomeostasis rather than VEGF inhibition, which may have implications for more specific treatment modalities in the acute phase of BRVO.
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Inhibidores de la Angiogénesis , Bevacizumab , Citocinas , Modelos Animales de Enfermedad , Inyecciones Intravítreas , Oclusión de la Vena Retiniana , Triamcinolona Acetonida , Animales , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Triamcinolona Acetonida/farmacología , Triamcinolona Acetonida/administración & dosificación , Triamcinolona Acetonida/uso terapéutico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Oclusión de la Vena Retiniana/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Citocinas/metabolismo , Citocinas/genética , Porcinos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Canales de Potasio de Rectificación InternaRESUMEN
BACKGROUND: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. METHODS: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or ß-adrenergic receptor (ß-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-ß (TGF-ß) receptor Type I kinase (Ly2157299) in vitro. TGF-ß1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. RESULTS: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-ß1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. CONCLUSIONS: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-ß1 signaling during this process. In addition, ß-AR/TGF-ß1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.
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Bevacizumab , Neoplasias Colorrectales , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neovascularización Patológica , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Neovascularización Patológica/metabolismo , Ratones , Factor de Crecimiento Transformador beta1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Propranolol/farmacología , Línea Celular Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Masculino , Movimiento Celular , Norepinefrina/farmacología , Norepinefrina/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Angiogénesis , Pirazoles , QuinolinasRESUMEN
Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.
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Acrilamidas , Afatinib , Compuestos de Anilina , Bevacizumab , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Acrilamidas/farmacología , Afatinib/farmacología , Afatinib/uso terapéutico , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Ratones , Humanos , Línea Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Modelos Animales de Enfermedad , Ensayos Antitumor por Modelo de Xenoinjerto , Receptores ErbB/metabolismo , Receptores ErbB/genética , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Piperazinas/farmacología , Piperazinas/uso terapéutico , Piperazinas/administración & dosificación , Femenino , Indoles , PirimidinasRESUMEN
Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody of VEGF, and inhibits angiogenesis and tumor growth in hepatocellular carcinoma (HCC). Ferroptosis, a new form of regulated cell death function independently of the apoptotic machinery, has been accepted as an attractive target for pharmacological intervention; the ferroptosis pathway can enhance cell immune activity of anti-PD1 immunotherapy in HCC. In this study we investigated whether and how bevacizumab regulated ferroptosis and immune activity in liver cancer. Firstly, we performed RNA-sequencing in bevacizumab-treated human liver cancer cell line HepG2 cells, and found that bevacizumab significantly altered the expression of a number of genes including VEGF, PI3K, HAT1, SLC7A11 and IL-9 in liver cancer, bevacizumab upregulated 37 ferroptosis-related drivers, and downregulated 17 ferroptosis-related suppressors in particular. We demonstrated that bevacizumab triggered ferroptosis in liver cancer cells by driving VEGF/PI3K/HAT1/SLC7A11 axis. Clinical data confirmed that the expression levels of VEGF were positively associated with those of PI3K, HAT1 and SLC7A11 in HCC tissues. Meanwhile, we found that bevacizumab enhanced immune cell activity in tumor immune-microenvironment. We identified that HAT1 up-regulated miR-143 targeting IL-9 mRNA 3'UTR in liver cancer cells; bevacizumab treatment resulted in the increase of IL-9 levels and its secretion via VEGF/PI3K/HAT1/miR-143/IL-9 axis, which led to the inhibition of tumor growth in vivo through increasing the release of IL-2 and Granzyme B from activated CD8+ T cells. We conclude that in addition to inhibiting angiogenesis, bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer. This study provides new insight into the mechanisms by which bevacizumab synergistically modulates ferroptosis and CD8+ T cell immune activity in liver cancer.
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Bevacizumab , Linfocitos T CD8-positivos , Ferroptosis , Neoplasias Hepáticas , Ferroptosis/efectos de los fármacos , Humanos , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Células Hep G2 , Microambiente Tumoral/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , MasculinoRESUMEN
Pathological ocular neovascularization resulting from retinal ischemia constitutes a major cause of vision loss. Current anti-VEGF therapies rely on burdensome intravitreal injections of Bevacizumab (Beva). Herein ultrasmall polymeric micelles encapsulating Beva (P@Beva) are developed for noninvasive topical delivery to posterior eye tissues. Beva is efficiently loaded into 11 nm micelles fabricated via self-assembly of hyperbranched amphiphilic copolymers. The neutral, brush-like micelles demonstrate excellent drug encapsulation and colloidal stability. In vitro, P@Beva enhances intracellular delivery of Beva in ocular cells versus free drug. Ex vivo corneal and conjunctival-sclera-choroidal tissues transport after eye drops are improved 23-fold and 7.9-fold, respectively. Anti-angiogenic bioactivity is retained with P@Beva eliciting greater inhibition of endothelial tube formation and choroid sprouting over Beva alone. Remarkably, in an oxygen-induced retinopathy (OIR) model, topical P@Beva matching efficacy of intravitreal Beva injection, is the clinical standard. Comprehensive biocompatibility verifies safety. Overall, this pioneering protein delivery platform holds promise to shift paradigms from invasive intravitreal injections toward simplified, noninvasive administration of biotherapeutics targeting posterior eye diseases.
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Inhibidores de la Angiogénesis , Bevacizumab , Micelas , Factor A de Crecimiento Endotelial Vascular , Animales , Bevacizumab/química , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Polímeros/química , Células Endoteliales de la Vena Umbilical Humana , Portadores de Fármacos/química , Administración Oftálmica , RatonesRESUMEN
OBJECTIVE: Glioblastoma (GBM) has poor clinical prognosis due to limited treatment options. In addition, the current treatment regimens for GBM may only slightly prolong patient survival. The aim of this study was to assess the role of BMAL1 in the immune microenvironment and drug resistance of GBM. METHODS: GBM cell lines with stable BMAL1 knockdown or LDHA overexpression were constructed, and functionally characterized by the CCK8, EdU incorporation, and transwell assays. In vivo GBM model was established in C57BL/6J mice. Flow cytometry, ELISA, immunofluorescence, and RT-qPCR were performed to detect macrophage polarization. Lactate production, pathological changes, and the expression of glycolytic proteins were analyzed by HE staining, immunohistochemistry, biochemical assays, and Western blotting. RESULTS: BMAL1 silencing inhibited the malignant characteristics, lactate production, and expression of glycolytic proteins in GBM cells, and these changes were abrogated by overexpression of LDHA or exogenous lactate supplementation. Furthermore, BMAL1 knockdown induced M1 polarization of macrophages, and inhibited M2 polarization and angiogenesis in GBM cells in conditioned media. Overexpression of LDHA or presence of exogenous lactate inhibited BMAL1-induced M1 polarization and angiogenesis. Finally, BMAL1 silencing and bevacizumab synergistically inhibited glycolysis, angiogenesis and M2 polarization, and promoted M1 polarization in vivo, thereby suppressing GBM growth. CONCLUSION: BMAL1 silencing can sensitize GBM cells to bevacizumab by promoting M1/M2 polarization through the LDHA/lactate axis.
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Factores de Transcripción ARNTL , Bevacizumab , Glioblastoma , Ácido Láctico , Ratones Endogámicos C57BL , Animales , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Glioblastoma/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Humanos , Línea Celular Tumoral , Bevacizumab/uso terapéutico , Bevacizumab/farmacología , Ratones , Ácido Láctico/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Resistencia a Antineoplásicos/genética , Microambiente Tumoral/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Glucólisis/efectos de los fármacos , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Neovascularización Patológica/genética , Neovascularización Patológica/tratamiento farmacológico , Silenciador del Gen , L-Lactato DeshidrogenasaRESUMEN
BACKGROUND: The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial. PATIENTS AND METHODS: In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed. RESULTS: Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS = 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS = 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS = 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P = 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P = 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P = 0.022). CONCLUSION: We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy.