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2022 ◽  
Vol 12 ◽  
Author(s):  
Qingli Cui ◽  
Yanhui Hu ◽  
Qingan Cui ◽  
Daoyuan Wu ◽  
Yuefeng Mao ◽  
...  

At present, treatment options for osimertinib resistance are very limited. Dual inhibition of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) significantly improved the progression-free survival (PFS) of advanced EGFR-mutant non–small cell lung cancer (NSCLC). After EGFR-tyrosine kinase inhibitor (TKI) resistance, EGFR-TKI continuation combined with VEGF inhibitors still had clinical benefits. It is unclear whether the addition of bevacizumab after osimertinib progresses will prolong the duration of the osimertinib benefit. We screened 1289 patients with NSCLC and finally included 96 patients to evaluate osimertinib combined with bevacizumab (osi + bev) versus chemotherapy combined with bevacizumab (che + bev) for patients with acquired resistance to osimertinib. The overall response rate (ORR) for osi + bev and chem + bev was 15.8% (6 of 38) and 20.7% (12 of 58), respectively. The median PFS for osi + bev and che + bev was 7.0 and 4.9 months (HR 0.415 95%CI: 0.252–0.687 p = 0.001). The median OS for osi + bev and che + bev was 12.6 and 7.1 months (HR 0.430 95%CI: 0.266–0.696 p = 0.001). Multivariate analyses showed that no brain metastases and osi + bev treatment after osimertinib resistance correlated with longer PFS (p = 0.044, p = 0.001), while the median PFS of osimertinib less than 6 months (p = 0.021) had a detrimental effect on sequent treatment. Only osi + bev treatment was identified as an independent predictor of OS (p = 0.001). The most common adverse events (AEs) of grade ≥3 were hypertension (13.2%) and diarrhea (10.5%) in the osi + bevacizumab group. Neutropenia (24.1%) and thrombocytopenia (19%) were the most common grade ≥3 AEs in the che + bev group. The overall incidence of serious AEs (grade ≥3) was significantly higher in the chemotherapy plus bevacizumab group. Our study has shown the superiority of osi + bev compared to che + bev after the failure of osimertinib, making it a preferred option for patients with acquired resistance to osimertinib.


2021 ◽  
Vol 17 (12) ◽  
pp. 2364-2373
Author(s):  
Song Wang ◽  
Zifeng Luo ◽  
Xinke Zhou ◽  
Chong Wang ◽  
Yuanwei Luo ◽  
...  

Breast cancer is still threatening many people’ lives, hence novel targeted therapies are urgently required to improve the poor outcome of breast cancer patients. Herein, our study aimed to explore the potential of nanoparticles (NPs)-loaded with VEGF inhibitors and MED1 siRNA for treatment of the disorder. PEG and MTC conjugates were synthesized by ion gelation, and equipped with VEGF inhibitor (siV) and MED1 (siD) siRNA (MT/PC/siV-D NPs). The size and morphology of the NPs were detected by TEM. Agarose gel experiment was performed to detect drug encapsulation rate and NPs stability. Zeta potential was assessed by immunofluorescence assay and cell uptake was detected by fluorescence analysis. After cancer cells were treated with NPs or PBS, cell proliferation and invasion were evaluated with VEGF and MED1 expression was detected by Western blot and RT-qPCR analyses. Animal model was conducted to confirm the role of NPs in tumor growth. Results showed that, the MT/PC/siV-D NPs exhibited great stability, drug encapsulation and internalization ability. The combined NPs caused decreased proliferation and invasion of tumor cells, inducing M2 macrophages to re-polarize to M1 type with declined expression of VEGF and MED1. Moreover, the NPs remarkably alleviated breast tumor progression. The multifunctional NPs equipped with EGF inhibitors and MED1 siRNA can inhibit tumor progression by targeting TAMs and cancer cells during breast cancer.


2021 ◽  
Author(s):  
Sourav Mukherjee ◽  
Mohnad Abdalla ◽  
Manasi Yadav ◽  
Maddala Madhavi ◽  
Ravina Khandelwal ◽  
...  

Abstract VEGF and its receptor play an important role both in physiologic and pathologic angiogenesis, which is identified in ovarian cancer progression and metastasis development. The aim of the present investigation is to identify a potential VEGF inhibitor which is playing a crucial role in stimulating the immunosuppressive microenvironment in tumour cells of ovary and to examine for an effectiveness of identified inhibitor for treatment of ovarian cancer using various In silico approaches. 12 established VEGF inhibitors were collected from various literature. The compound AEE788 displays the great affinity towards the target protein as a result of docking study. AEE78 was further used for structure base virtual screening in order to obtain more structurally similar compound with high affinity. Among the 80 Virtual screened compounds, CID 88265020, explicates much better affinity than established compound AEE788. Based on Molecular Dynamics Simulation, pharmacophore and comparative toxicity analysis of both the best established compound and the best virtual screened compound displayed a trivial variation in associated properties. The virtual screened compound CID 88265020 have the high affinity with the lowest re-rank score, and holds a huge potential to inhibit the VGFR and can be implemented for prospective of future investigations in Ovarian Cancer.


2021 ◽  
Vol 11 (1) ◽  
pp. e4-e4
Author(s):  
Shirinsadat Badri ◽  
Lillian Siberian ◽  
Rasool Soltani ◽  
Azadeh Moghaddas ◽  
Sara Ataei ◽  
...  

Vascular endothelial growth factor (VEGF) is a special mitogen for vascular endothelial cells, an essential endogenous angiogenic cytokine, and the principal controller of vascular growth that plays a fundamental role in therapeutic angiogenesis pathways. VEGF-targeted therapy is categorized into the group of angiogenesis inhibitors that inhibit the expression or the activity of VEGF. It comprises counteracting VEGF antibodies, VEGF receptors, VEGF-trap, and tyrosine kinase inhibitor (TKIs) with selectivity for VEGF receptors. The kidney is both a target and a source of VEGF. VEGF may be a vital mediator to restore some types of renal diseases (e.g., non-diabetic renal diseases) and harmful in some other diseases (e.g., diabetes and diabetes complications). Due to their ability to prevent angiogenesis, VEGF inhibitors have been found as a powerful tool to treat angiogenesis-dependent diseases, including cancer and diabetic retinopathy. VEGF preserves the renal structure and function in normal physiologic conditions. Therefore, all treatments that inhibit the VEGF pathway may lead to renal disorders, especially renovascular diseases such as hypertension, proteinuria, nephrotic syndrome, decreased glomerular filtration rate (GFR), and thrombotic microangiopathy (TMA). In the present study, we reviewed some related reports and associated mechanisms, especially for hypertension and proteinuria.


2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
L Van Doorn ◽  
W J Visser ◽  
D C H Van Dorst ◽  
K M M Mirabito Colafella ◽  
S L W Koolen ◽  
...  

Abstract Introduction Vascular endothelial growth factor (VEGF) inhibitors target the formation of new blood vessels required for growth and metastatic spread of a malignant tumor. Although this is an effective anticancer treatment, many patients develop cardiovascular side effects such as hypertension, requiring dose reduction or early termination of treatment. In animals, VEGF inhibitor-induced hypertension is salt-sensitive. Aim To prospectively study whether salt restriction can prevent or attenuate the rise in blood pressure in response to anti-cancer treatment with VEGF inhibitors. Method This is a single centre prospective open-label intervention study. Patients are eligible when treated with a VEGF inhibitor according to standard of care and developing hypertension or a blood pressure rises of 20 mmHg or more during the first treatment cycle. A salt restricted diet (<4 grams/day) including provided salt-less bread is started during the off-treatment period under guidance of a specialized dietitian. The primary endpoint is mean difference in blood pressure rise between the treatment cycle with and the treatment cycle without salt restriction. We aim for a total of 16 patients with a blood pressure rise of at least 20mmHg and/or development of hypertension undergoing the intervention. Results Between 28 November 2019 and 25 March 2021, 45 patients gave informed consent. Fourteen patients developed hypertension and/or a blood pressure rise of at least 20 mmHg after three- four weeks of treatment making them eligible for the intervention. In 10 patients, salt restriction was the only intervention to reduce the blood pressure rise during the following treatment cycle, leading to a reduction in blood pressure rise of 17 mmHg (10 vs 27 mmHg; p<0.001). In four patients antihypertensive treatment was started during the first treatment cycle due to blood pressure rise above 170 mmHg. Salt restriction did not appear to have an important further blood pressure lowering effect, although in one patient the antihypertensive treatment was interrupted during the stop week and salt restriction was sufficient to limit the blood pressure rise in the second cycle. Importantly, the intervention was well tolerated and most patients continued salt restriction after the study finished. Conclusion Applying salt restriction might be an effective and well tolerated intervention to decrease blood pressure rise during treated with VEGF inhibitors. More importantly, this gives important information about the pathogenesis. Further studies of collected blood and 24h urine samples will allow conclusions on the role of endothelin-1, the renin aldosterone system and prostacyclins. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): De Merel (Charity aiming for research directly benefiting patients; yearly award, success rate ∼30% “Stichting De Merel”)


2021 ◽  
Vol 10 (18) ◽  
pp. 4133
Author(s):  
Slawomir Jan Teper

Uveitic macular edema (ME) is a frequent complication in 8.3% of uveitis patients and is a leading cause of serious visual impairment in about 40% of cases. Despite the numerous available drugs for its treatment, at least a third of patients fail to achieve satisfactory improvement in visual acuity. First-line drugs are steroids administered by various routes, but drug intolerance or ineffectiveness occur frequently, requiring the addition of other groups of therapeutic drugs. Immunomodulatory and biological drugs can have positive effects on inflammation and often on the accompanying ME, but most uveitic randomized clinical trials to date have not aimed to reduce ME; hence, there is no clear scientific evidence of their effectiveness in this regard. Before starting therapy to reduce general or local immunity, infectious causes of inflammation should be ruled out. This paper discusses local and systemic drugs, including steroids, biological drugs, immunomodulators, VEGF inhibitors, and anti-infection medication.


2021 ◽  
Author(s):  
Jesus Hernan Gonzalez-Cortes ◽  
Jesus Emiliano Gonzalez-Cantu ◽  
Aditya Sudhalkar ◽  
Sergio Eustolio Hernandez-Da Mota ◽  
Alper Bilgic ◽  
...  

Diabetes mellitus is a global epidemic that leads to multiple macrovascular and microvascular complications. The complex interrelated pathophysiological mechanisms triggered by hyperglycemia underlie the development of diabetic retinopathy (DR). Proliferative diabetic retinopathy (PDR) is a microvascular complication, considered the main cause of irreversible blindness in patients of productive age in the world. On the other hand, diabetic macular edema (DME) remains the clinical feature most closely associated with vision loss. In general, both manifestations are due to an increase in inflammatory factors, such as specific pro-inflammatory prostaglandins, interleukins and angiogenic substances including vascular endothelial growth factor (VEGF). Laser photocoagulation and VEGF inhibitors have been shown to be effective in the treatment of PDR and DME. Currently, randomized protocols suggest that VEGF inhibitors therapy could displace laser photocoagulation in the treatment of PDR with and without the presence of DME. The ongoing discussion still prevails about the different treatment modalities for both retinal manifestations in real-world settings.


Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Karla B Neves ◽  
Rheure Alves-lopes ◽  
Ninian Lang ◽  
Augusto C Montezano ◽  
Rhian M Touyz

Hypertension is a common unwanted effect of VEGF inhibitors (VEGFi), which are used as anti-angiogenic drugs in cancer treatment. Clinical observations suggest that the combination of VEGFi with another anti-cancer drug, olaparib (PARP inhibitor [PARPi]), may attenuate the development of hypertension. However putative vascular mechanisms are unknown. PARP plays a major role in the activation of TRPM2, a redox-sensitive Ca 2+ channel, which is associated with hypertension-induced vascular dysfunction. We hypothesized that PARPi attenuates VEGFi-induced vascular injury through TRPM2/Ca 2+ -dependent pathways. Human vascular smooth muscle cells (hVSMC), human aortic endothelial cells (HAEC), and mouse mesenteric arteries were studied. Cells/arteries were exposed to axitinib (VEGFi) alone (3μM) or in combination with olaparib (1μM). Wire myography was used to assess vascular function. Axitinib reduced ACh-induced vasodilation (% relaxation: 70.5 [Ct] vs. 34.8 [Axi]), an effect blocked by olaparib. U46619- and ET-1-induced vasoconstriction were increased by axitinib (% KCl- U4 : 101.2 [Ct] vs. 141.4 [Axi]; ET-1 : 122.6 [Ct] vs. 152.5 [Axi]), an effect not observed with axitinib plus olaparib. TRPM2 channel blocker (8-Br-cADPR; 1μM) attenuated the hypercontractile effects and endothelial dysfunction induced by axitinib. Axitinib increased ROS production in hVSMC (RUL: 0.8±0.2 [Ct] vs. 1.1±0.09 [Axi]) and HAEC (0.7±0.4 [Ct] vs. 1.2±0.1 [Axi]), stimulated phosphorylation of the inhibitory site of eNOS (a.u.: 0.99±0.35 [Ct] vs. 1.35±0.10 [Axi]) and induced exaggerated Ca 2+ influx (AUC: 17541±4708 [Ct] vs. 22249±1438 [Axi]) in hVSMC. These effects were blocked by olaparib and 8-Br-cADPR. Axitinib also induced phosphorylation of MLC20 in hVSMC (a.u.: 0.028±0.02 [Ct] vs. 0.04±0.01 [Axi]) and aorta (a.u.: 0.3±0.01 [Ct] vs. 0.5±0.001 [Axi]). Our data indicate that PARP/TRPM2 inhibition attenuates axitinib-mediated vascular dysfunction and normalizes impaired hVSMC and HAEC signalling induced by VEGFi. We define a putative vasoprotective effect of olaparib that may ameliorate vascular injury and hypertension induced by VEGFi in cancer treatment.


Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 919
Author(s):  
Eun-mi Yu ◽  
Laura Linville ◽  
Matthew Rosenthal ◽  
Jeanny B. Aragon-Ching

The use of checkpoint inhibitors in advanced and metastatic renal cell carcinomas (RCCs) has rapidly evolved over the past several years. While immune-oncology (IO) drug therapy has been successful at resulting in improved responses and survival, combination therapies with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors have further improved outcomes. This article reviews the landmark trials that have led to the approval of IO therapies, including the Checkmate 214 trial and combination IO/VEGF TKI therapies with Checkmate 9ER, CLEAR, and Keynote-426, and it includes a discussion on promising therapies moving in the future.


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