Pharmacological interventions for intraplaque neovascularization in atherosclerosis.

Advanced atherosclerosis is linked to plaque instability, which can result in rupture and the onset of a heart attack. Evidence gathered from human atheroma plaques indicates that intraplaque neovascularization poses a risk to plaque stability and may lead to plaque hemorrhage. Hence, targeting the neovascularization within the atheroma plaque has the potential to mitigate the plaque's vulnerability. While neovascularization has been extensively explored in the context of cancer, research on pharmacological inhibition of this phenomenon in atherosclerosis remains limited. This systematic review aimed to comprehensively assess current and emerging pharmacological interventions for inhibiting intraplaque neovascularization in preclinical settings. Electronic databases (Web of Science, PubMed, Scopus, and Ovid) were searched from January 2013 until February 1, 2024. Preclinical studies reporting the effect of any pharmacological interventions targeting intraplaque neovascularization were included. A total of 10 articles involving in vivo animal studies were eligible for inclusion, with five of them incorporating in vitro experiments to complement their in vivo findings. The pharmacological interventions studied were axitinib, ghrelin, K5, rosuvastatin, atorvastatin, 3PO, everolimus, melatonin, Si-Miao-Yong-A, and protocatechuic aldehyde. All the interventions showed a positive impact in inhibiting intraplaque neovascularization in various atherosclerotic animal models through various signaling pathways. This review provides valuable insights into pharmacological approaches to attenuate intraplaque neovascularization that could serve as a promising therapeutic avenue to enhance plaque stability.

New hopes and promises in the treatment of ovarian cancer focusing on targeted treatment-a narrative review.

Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that treated patients have a high risk of disease recurrence. Moreover, ovarian cancer is very diverse in terms of molecular, histological features and mutations. Many patients may also develop platinum resistance, resulting in poor response to subsequent lines of treatment. To improve the prognosis of patients with ovarian cancer, it is expected to make better existing and implement new, promising treatment methods. Targeted therapies seem very promising. Currently, bevacizumab - a VEGF inhibitor and therapy with olaparib - a polyADP-ribose polymerase inhibitor are approved. Other methods worth considering in the future include: folate receptor α, immune checkpoints or other immunotherapy methods. To improve the treatment of ovarian cancer, it is also important to ameliorate the determination of molecular features to describe and understand which group of patients will benefit most from a given treatment method. This is important because a larger group of patients treated for ovarian cancer can have a greater chance of surviving longer without recurrence.

[Anatomical and functional outcomes of the "3+PRN" therapeutic protocol in the treatment of diabetic macular edema]. / Résultats anatomiques et fonctionnels du protocole thérapeutique « 3+PRN ¼ dans le traitement de l'œdème maculaire diabétique.

PURPOSE: To evaluate the anatomical and functional results of the "3+PRN" protocol in the treatment of diabetic macular edema (DME), determine the predictive factors for good final visual acuity, and compare it to other protocols. MATERIALS AND METHODS: We conducted a retrospective, descriptive, comparative, cross-sectional study of patients with DME, which we dubbed HTSM. All patients were treated with three monthly initial intravitreal injections (IVT) of 1.25mg bevacizumab and followed according to the pro re nata (PRN) protocol for a period of 3years. The protocol was based on a monthly monitoring schedule for the first 3months, then increasingly spaced out over time. "On-demand" treatment was indicated with resumption of bevacizumab IVT in the event of worsening of DME. RESULTS: A total of 52 patients were included. The mean age was 65years. Type 2 was the most frequently observed type of diabetes. The mean duration of the PRN protocol was 6months, and the mean number of injections was 6. The mean visual acuity (VA), initially 1/10, improved to 3/10 by the conclusion of the 3+PRN protocol, with an improvement of more than 5 letters in 77.6% of cases. The mean initial central macular thickness (CMT) was 451.5µm. The final mean EMC decreased to 298.5µm, which corresponds to a reduction of 153µm compared to the initial value. The mean subfoveal choroidal thickness, initially 304.2µm, decreased to a mean of 284.5µm at completion. Comparative analysis of the results before and after the PRN protocol confirmed the existence of a statistically significant correlation between VA and CMT (P<0.05). No correlation was observed between age and visual acuity or between initial and final VA. The analysis of the various tomographic parameters and VA revealed a significantly better visual improvement in the group in whom the external limiting membrane (MLE) and ellipsoid zone (ZE) were intact (P=0.04), as well as in the group in whom serous retinal detachment (SRD) was absent (P<0.001). Posterior vitreous detachment (PVD) was the most frequently observed vitreomacular anomaly. The final VA was similar in the groups with and without PVD (P=0.04). CONCLUSION: The 3+PRN protocol is effective both functionally and tomographically in the treatment of DME. Various tomographic parameters might influence therapeutic efficacy. However, further in-depth studies are needed to better investigate these parameters.

An Overview of Cancer Biology, Pathophysiological Development and It's Treatment Modalities: Current Challenges of Cancer anti-Angiogenic Therapy.

A number of conditions and factors can cause the transformation of normal cells in the body into malignant tissue by changing the normal functions of a wide range of regulatory, apoptotic, and signal transduction pathways. Despite the current deficiency in fully understanding the mechanism of cancer action accurately and clearly, numerous genes and proteins that are causally involved in the initiation, progression, and metastasis of cancer have been identified. But due to the lack of space and the abundance of details on this complex topic, we have emphasized here more recent advances in our understanding of the principles implied tumor cell transformation, development, invasion, angiogenesis, and metastasis. Inhibition of angiogenesis is a significant strategy for the treatment of various solid tumors, that essentially depend on cutting or at least limiting the supply of blood to micro-regions of tumors, leading to pan-hypoxia and pan-necrosis inside solid tumor tissues. Researchers have continued to enhance the efficiency of anti-angiogenic drugs over the past two decades, to identify their potential in the drug interaction, and to discover reasonable interpretations for possible resistance to treatment. In this review, we have discussed an overview of cancer history and recent methods use in cancer therapy, focusing on anti-angiogenic inhibitors targeting angiogenesis formation. Further, this review has explained the molecular mechanism of action of these anti-angiogenic inhibitors in various tumor types and their limitations use. In addition, we described the synergistic mechanisms of immunotherapy and anti-angiogenic therapy and summarizes current clinical trials of these combinations. Many phase III trials found that combining immunotherapy and anti-angiogenic therapy improved survival. Therefore, targeting the source supply of cancer cells to grow and spread with new anti-angiogenic agents in combination with different conventional therapy is a novel method to reduce cancer progression. The aim of this paper is to overview the varying concepts of cancer focusing on mechanisms involved in tumor angiogenesis and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy.

Comparison between Nivolumab and Regorafenib as Second-line Systemic Therapies after Sorafenib Failure in Patients with Hepatocellular Carcinoma.

PURPOSE: Nivolumab and regorafenib are second-line therapies for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the effectiveness of nivolumab and regorafenib. MATERIALS AND METHODS: We retrospectively reviewed patients with HCC treated with nivolumab or regorafenib after sorafenib failure. Progression-free survival (PFS) and overall survival (OS) were analyzed. An inverse probability of treatment weighting using the propensity score (PS) was performed to reduce treatment selection bias. RESULTS: Among the 189 patients recruited, 137 and 52 patients received regorafenib and nivolumab after sorafenib failure, respectively. Nivolumab users showed higher Child-Pugh B patients (42.3% vs. 24.1%) and shorter median sorafenib maintenance (2.2 months vs. 3.5 months) compared to regorafenib users. Nivolumab users showed shorter median OS (4.2 months vs. 7.4 months, p=0.045) than regorafenib users and similar median PFS (1.8 months vs. 2.7 months, p=0.070). However, the median overall and PFS did not differ between the two treatment groups after the 1:1 PS matching (log-rank p=0.810 and 0.810, respectively) and after the stabilized inverse probability of treatment weighting (log-rank p=0.445 and 0.878, respectively). In addition, covariate-adjusted Cox regression analyses showed that overall and PFS did not significantly differ between nivolumab and regorafenib users after 1:1 PS matching and stabilized inverse probability of treatment weighting (all p>0.05). CONCLUSION: Clinical outcomes of patients treated with nivolumab and regorafenib after sorafenib treatment failure did not differ significantly.

Immune-related adverse events of immune checkpoint inhibitors combined with angiogenesis inhibitors: A real-world pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database (2014-2022).

INTRODUCTION: Although immune checkpoint inhibitors (ICIs) combined with angiogenesis inhibitors (AGIs) has become increasingly used for cancers, the impact of combination therapy on immune-related adverse events (irAEs) in real-world settings has not been well elucidated to date. METHODS: The FDA Adverse Event Reporting System (FAERS) database from 2014 to 2022 was retrospectively queried to extract reports of irAEs referred as standardized MedDRA queries (SMQs), preferred terms (PTs) and system organ classes (SOCs). To perform disproportionality analysis, information component (IC) and reporting odds ratio (ROR) were calculated and lower limit of 95 % confidence interval (CI) for IC (IC025) > 0 or ROR (ROR025) > 1 with at least 3 reports was considered statistically significant. RESULTS: Compared to ICIs alone, ICIs + AGIs demonstrated a lower IC025/ROR025 for irAEs-SMQ (2.343/5.082 vs. 1.826/3.563). Regarding irAEs-PTs, there were fewer irAEs-PTs of significant value in ICIs + AGIs than ICIs alone (57 vs. 150 PTs) and lower signal value for most PTs (88 %) in ICIs + AGIs. Moreover, lower IC025 for most of irAEs-SOCs in ICIs + AGIs (11/13) compared with ICIs alone was observed. As for outcomes of irAEs, ICIs + AGIs showed a lower frequency of "fatal" for irAEs-SMQ than ICIs alone (4.88 % vs. 7.83 %), so as in cardiac disorder (SOC) (15.45 % vs. 26.37 %), and respiratory, thoracic and mediastinal disorders (SOC) (13.74 % vs. 20.06 %). Similarly, there were lower occurrence and fewer fatality of irAEs in ICIs + AGIs + chemotherapy (CT) than ICIs + CT. CONCLUSION: ICIs combined with AGIs may reduce incidence and mortality for most of irAEs compared to ICIs alone whether or not with CT.

Novel angiogenesis inhibitors with superoxide anion radical amplification effect: Surmounting the Achilles' heels of angiogenesis inhibitors and photosensitizers.

Angiogenesis inhibitors and photosensitizers are pivotal in tumor clinical treatment, yet their utilization is constrained. Herein, eleven novel angiogenesis inhibitors were developed through hybridization strategy to overcome their clinical limitations. These title compounds boast excitation wavelengths within the "therapeutic window", enabling deep tissue penetration. Notably, they could generate superoxide anion radicals via the Type I mechanism, with compound 36 showed the strongest superoxide anion radical generating capacity. Biological evaluation demonstrated remarkable cellular activity of all the title compounds, even under hypoxic conditions. Among them, compound 36 stood out for its superior anti-proliferative activity in both normoxic and hypoxic environments, surpassing individual angiogenesis inhibitors and photosensitizers. Compound 36 induced cell apoptosis via superoxide anion radical generation, devoid of dark toxicity. Molecular docking revealed that the target-recognizing portion of compound 36 was able to insert into the ATP binding pocket of the target protein similar to sorafenib. Collectively, our results suggested that hybridization of angiogenesis inhibitors and photosensitizers was a potential strategy to address the limitations of their clinical use.

A case report of low-dose apatinib in the treatment of advanced triple-negative breast cancer.

Background: The current study shows that the incidence rate of triple-negative breast cancer accounts for 10-17% of invasive ductal carcinoma of the breast. There is no specific treatment target, the age of onset is relatively small, and the recurrence rate is relatively fast. The prognosis of breast cancer in different subtypes is the most unsatisfactory, with a 5-year survival rate of less than 15%. We report a typical case of metastatic advanced triple-negative breast cancer who responded well to apatinib mesylate after chemotherapy failure and achieved significant progression-free survival, which is relatively rare in triple-negative breast cancer with limited treatment means. Case Description: A 55-year-old female was surgically diagnosed as triple-negative breast cancer on April 17, 2015. After surgery, she had lung metastasis after standard adjuvant chemotherapy and radiotherapy. After receiving the NX regimen (vinorelbine, capecitabine) for 8 cycles, she progressed. Because the patient refused later, she was adjusted to apatinib mesylate, and serious adverse reactions occurred during the treatment process. By adjusting the drug dose, and low-dose apatinib treatment, the lung lesions were close to complete response (CR), reaching a progression-free survival period of 45 months. Conclusions: Low-dose apatinib may be a promising anti-tumor drug for triple-negative breast cancer patients, which needs more samples to verify. This case may provide a reference for the treatment selection of triple-negative metastatic breast cancer in the future.

[Pharmacoeconomic analysis of anti-angiogenic drugs for diabetic macular edema]. / Farmakoekonomicheskii analiz primeneniya antiangiogennykh preparatov pri diabeticheskom makulyarnom oteke.

Diabetic macular edema (DME) is a degenerative disease of the macular area in diabetes mellitus and can lead to vision loss, disability, and significantly reduced quality of life. Faricimab is the only bispecific antibody for DME therapy that targets two pathogenic pathways (Ang-2 and VEGF-A). PURPOSE: This study comparatively evaluates the clinical and economic feasibility of faricimab and other angiogenesis inhibitors in patients with DME. MATERIAL AND METHODS: This article analyzed literature on the efficacy and safety of intravitreal injections (IVI) of ranibizumab 0.5 mg, aflibercept 2 mg, and faricimab 6 mg. A model of medical care was developed for patients with DME receiving anti-angiogenic therapy. Pharmacoeconomic analysis was performed using cost minimization and budget impact analysis (BIA) methods. Modeling time horizon was 2 years. The research was performed from the perspective of the healthcare system of the Russian Federation. RESULTS: The efficacy and safety of faricimab in a personalized regimen (up to one IVI in 16 weeks) are comparable to those of aflibercept and ranibizumab, administered in various regimens. The use of faricimab is associated with the lowest number of IVIs. Over 2 years, the maximum costs of drug therapy were associated with the use of ranibizumab (about 914 thousand rubles), while the minimum costs were associated with the use of faricimab (614 thousand rubles). The reduction in inpatient care costs with faricimab therapy was 36% compared to aflibercept (216 and 201 thousand rubles in inpatient and day hospitals, respectively) and 82% compared to ranibizumab (486 and 451 thousand rubles in inpatient and day hospitals, respectively). BIA demonstrated that the use of faricimab will reduce the economic burden on the healthcare system by 11.3 billion rubles (9.8%) over 2 years. CONCLUSION: The use of faricimab is a cost-effective approach to treatment of adult patients with DME in Russia.

Magnetic resonance imaging-based approaches for detecting the efficacy of combining therapy following VEGFR-2 and PD-1 blockade in a colon cancer model.

BACKGROUND: Angiogenesis inhibitors have been identified to improve the efficacy of immunotherapy in recent studies. However, the delayed therapeutic effect of immunotherapy poses challenges in treatment planning. Therefore, this study aims to explore the potential of non-invasive imaging techniques, specifically intravoxel-incoherent-motion diffusion-weighted imaging (IVIM-DWI) and blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), in detecting the anti-tumor response to the combination therapy involving immune checkpoint blockade therapy and anti-angiogenesis therapy in a tumor-bearing animal model. METHODS: The C57BL/6 mice were implanted with murine MC-38 cells to establish colon cancer xenograft model, and randomly divided into the control group, anti-PD-1 therapy group, and combination therapy group (VEGFR-2 inhibitor combined with anti-PD-1 antibody treatment). All mice were imaged before and, on the 3rd, 6th, 9th, and 12th day after administration, and pathological examinations were conducted at the same time points. RESULTS: The combination therapy group effectively suppressed tumor growth, exhibiting a significantly higher tumor inhibition rate of 69.96% compared to the anti-PD-1 group (56.71%). The f value and D* value of IVIM-DWI exhibit advantages in reflecting tumor angiogenesis. The D* value showed the highest correlation with CD31 (r = 0.702, P = 0.001), and the f value demonstrated the closest correlation with vessel maturity (r = 0.693, P = 0.001). While the BOLD-MRI parameter, R2* value, shows the highest correlation with Hif-1α(r = 0.778, P < 0.001), indicating the capability of BOLD-MRI to evaluate tumor hypoxia. In addition, the D value of IVIM-DWI is closely related to tumor cell proliferation, apoptosis, and infiltration of lymphocytes. The D value was highly correlated with Ki-67 (r = - 0.792, P < 0.001), TUNEL (r = 0.910, P < 0.001) and CD8a (r = 0.918, P < 0.001). CONCLUSIONS: The combination of VEGFR-2 inhibitors with PD-1 immunotherapy shows a synergistic anti-tumor effect on the mouse colon cancer model. IVIM-DWI and BOLD-MRI are expected to be used as non-invasive approaches to provide imaging-based evidence for tumor response detection and efficacy evaluation.

Risk of cardiovascular toxicity with combination of immune-checkpoint inhibitors and angiogenesis inhibitors: a meta-analysis.

Introduction: Combinations of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AIs) have been investigated for the treatment of several tumor types. Both ICIs and AIs may lead to cardiovascular adverse events, and their combination may potentially increase the risk for cardiovascular toxicity. In the present meta-analysis, we aim to assess the cardiovascular toxicity of ICIs plus AIs vs. AIs alone. Secondary objectives are non-cardiovascular adverse events and efficacy. Methods: Systematic review was performed according to PRISMA statement. Phase II and III randomized clinical trials were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts, from inception to June 2022. The pooled risks for overall response rate (ORR), 1-year progression-free survival (PFS), adverse events (AEs), immune-related AEs, (irAEs), hypertension, and vascular events defined as stroke, myocardial infarction and pulmonary embolisms, were calculated. Results: In terms of cardiovascular toxicity, we found higher risk for severe hypertension among patients treated with ICIs plus AIs as compared with those receiving AIs (OR 1.24, 95% CI: 1.01-1.53), but no significant difference was found for any-grade hypertension, and for vascular events. There was also no difference in terms of overall AEs, whereas the incidence of irAEs was increased in the ICIs plus AIs arm, as expected. In terms of efficacy, ICIs plus AIs achieved better ORR (OR 2.25, 95% CI: 1.70-2.97) and PFS (HR 0.49, 95% CI: 0.39-0.63) as compared to AIs alone. Conclusion: The addition of ICIs to AIs significantly increased the risk of high-grade hypertension, but not that of acute vascular events.

Novel multi-target angiogenesis inhibitors as potential anticancer agents: Design, synthesis and preliminary activity evaluation.

Based on the crucial role of histone deacetylase (HDAC) and receptor tyrosine kinase in angiogenesis, in situ assembly, skeletal transition, molecular hybridization, and pharmacophore fusion were employed to yield seventy-six multi-target angiogenesis inhibitors. Biological evaluation indicated that most of the compounds exhibited potent proliferation inhibitory activity on MCF-7 cells, with the TH series having the highest inhibitory activity on MCF-7 cells. In addition, the IC50 values of TA11 and TH3 against HT-29 cellswere 0.078 µmol/L and 0.068 µmol/L, respectively. The cytotoxicity evaluation indicated that TC9, TA11, TM4, and TH3 displayed good safety against HEK293T cells. TH2 and TH3 could induce apoptosis of MCF-7 cells. Molecular modeling and ADMET prediction results indicated that most of target compounds showed promising medicinal properties, which was consistent with the experimental results. Our findings provided new lead compounds for the structural optimization of multi-target angiogenesis inhibitors.

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma (uHCC). HAIC-based treatment showed great potential for treating uHCC. However, large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking. AIM: To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors, programmed cell death of protein 1 (PD-1) and its ligand (PD-L1) blockers (triple therapy) under real-world conditions. METHODS: Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis. Study-level pooled analyses of hazard ratios (HRs) and odds ratios (ORs) were performed. This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades (AIPB) at Sun Yat-sen University Cancer Center from January 2018 to April 2023. Propensity score matching (PSM) was performed to balance the bias between the groups. The Kaplan-Meier method and cox regression were used to analyse the survival data, and the log-rank test was used to compare the suvival time between the groups. RESULTS: A total of 13 randomized controlled trials were included. HAIC alone and in combination with sorafenib were found to be effective treatments (P values for ORs: HAIC, 0.95; for HRs: HAIC + sorafenib, 0.04). After PSM, 176 HCC patients were included in the analysis. The triple therapy group (n = 88) had a longer median overall survival than the AIPB group (n = 88) (31.6 months vs 14.6 months, P < 0.001) and a greater incidence of adverse events (94.3% vs 75.4%, P < 0.001). CONCLUSION: This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC. Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Comparison of antiangiogenic agents (ranibizumab, aflibercept, bevacizumab and ziv-aflibercept) in the therapeutic response to the exudative form of age-related macular degeneration according to the treat-and-extend protocol- true head-to-head study.

PURPOSE: To evaluate the structural and functional changes in eyes with neovascular age related macular degeneration (nAMD) in a real-world setting, using Treat and Extend protocol (T&E), comparing four antiangiogenic agents. METHODS: Prospective, observational, case series study performed in 131 patients with the exudative form of nAMD. Patients were randomly assigned into four groups according to the antiangiogenic agent. During the first year, all eyes received at least 3 monthly intravitreal injections of antiangiogenic agents, and afterwards, were submitted to the T&E. RESULTS: There was statistically significant difference (p < 0.05) between pre- and post-treatment in the best corrected visual acuity measurements by drug used. Patients who used aflibercept had significantly fewer injections than patients using the other drugs (mean = 9.03). No significant difference was observed between the drugs bevacizumab, ranibizumab and ziv-aflibercept. With regard to biomarkers, patients who used aflibercept and had lower baseline central retinal thickness, absence of hyperreflective foci and no subretinal hyperreflective material had the lowest number of injections. CONCLUSION: Results indicate that over 2 years, Intravitreal aflibercept on T&E provided better visual and anatomical improvements when compared to other drugs used in this study with significantly fewer injections.

Novel Products as Promising Therapeutic Agents for Angiogenesis Inhibition.

OBJECTIVE: Angiogenesis is the process of forming new blood vessels from pre-existing vessels and occurs during development, wound healing, and tumor growth. In this review, we aimed to present a comprehensive view of various factors contributing to angiogenesis during carcinogenesis. Anti-angiogenesis agents prevent or slow down cancer growth by interrupting the nutrients and blood supply to the tumor cells, and thus can prove beneficial for treatment. METHOD: The discovery of several novel angiogenic inhibitors has helped to reduce both morbidity and mortality from several life-threatening diseases, such as carcinomas. There is an urgent need for a new comprehensive treatment strategy combining novel anti-angiogenic agents for the control of cancer. The article contains details of various angiogenic inhibitors that have been adopted by scientists to formulate and optimize such systems in order to make them suitable for cancer. RESULTS: The results of several researches have been summarized in the article and all of the data support the claim that anti-angiogenic agent is beneficial for cancer treatment. CONCLUSION: This review focuses on novel antiangiogenic agents that play a crucial role in controlling carcinogenesis.

Nonsynonymous mutations in VEGF receptor binding domain alter the efficacy of bevacizumab treatment.

Vascular endothelial growth factor (VEGF) mediated angiogenesis is crucial for tumor progression. Isoforms of VEGF bind to different VEGF receptors (VEGFRs) to initiate angiogenesis specific cellular signaling. Inhibitors that target both the receptors and ligands are in clinical use to impede angiogenesis. Bevacizumab, a monoclonal antibody (mAb) approved by the Food and Drug Administration (FDA), binds in the VEGF receptor binding domain (RBD) of all soluble isoforms of VEGF and inhibits the VEGF-VEGFR interaction. Bevacizumab is also used in combination with other chemotherapeutic agents for a better therapeutic outcome. Understanding the intricate polymorphic character of VEGFA gene and the influence of missense or nonsynonymous mutations in the form of nonsynonymous polymorphisms (nsSNPs) on RBD of VEGF may aid in increasing the efficacy of this drug. This study has identified 18 potential nsSNPs in VEGFA gene that affect the VEGF RBD structure and alter its binding pattern to bevacizumab. The mutated RBDs, modeled using trRosetta, in addition to the changed pattern of secondary structure, post translational modification and stability compared to the wild type, have shown contrasting binding affinity and molecular interaction pattern with bevacizumab. Molecular docking analysis by ClusPro and visualization using PyMol and PDBsum tools have detected 17 nsSNPs with decreased binding affinity to bevacizumab and therefore may impact the treatment efficacy. Whereas VEGF RBD expressed due to rs1267535717 (R229H) nsSNP of VEGFA has increased affinity to the mAb. This study suggests that genetic characterization of VEGFA before bevacizumab mediated cancer treatment is essential in predicting the appropriate efficacy of the drug, as the treatment efficiency may vary at individual level.

Reclassification of therapeutic response of unresectable hepatocellular carcinoma to anti-angiogenic therapy and immunotherapy using alpha RECIST.

OBJECTIVES: To assess the therapeutic response of HCC to antiangiogenic therapy plus immunotherapy by integrating RECIST 1.1 and alpha-fetoprotein (AFP) response at the 6th week to predict overall survival (OS). METHODS: This retrospective study included 150 and 214 patients with HCC who received combination therapy in training and validation cohorts. The medical images and AFP levels obtained at baseline and 6th week were collected. AFP response stratification: partial response (PR): AFP% ≥ 75% decline; stable disease (SD): AFP% < 75% decline and ≤ 10% elevation; progressive disease (PD): AFP% > 10% elevation. The alpha-RECIST was: PR: RECIST 1.1-PR or AFP-PR; PD: AFP-PD or RECIST 1.1-PD and does not satisfy AFP-PR; SD: neither PR nor PD. OS was compared using Kaplan-Meier curves. The predictive ability of various criteria was evaluated using the concordance index and time-dependent area under the receiver-operating characteristic curve. RESULTS: RECIST 1.1 achieved significant OS stratification (p = 0.020) for AFP < 20 ng/mL. For AFP ≥ 20 ng/mL, alpha-RECIST showed better performance than RECIST 1.1, mRECIST, and AFP response according to C-index (0.73 vs 0.66 vs 0.68 vs 0.69). The National Cancer Center (NCC) strategy utilized RECIST 1.1 for AFP < 20 ng/mL and alpha-RECIST for AFP ≥ 20 ng/mL and showed better performance than RECIST 1.1, mRECIST and AFP response according to C-index (0.73 vs 0.67 vs 0.69 vs 0.64). The performances of alpha-RECIST and NCC Strategy were confirmed in the validation cohort (C-index = 0.77 and 0.74). CONCLUSIONS: The alpha-RECIST and NCC Strategy achieved better survival stratification in patients with HCC under combination therapy in the AFP ≥ 20 ng/mL group and the whole cohort compared to the RECIST 1.1, mRECIST, and AFP response. CLINICAL TRANSLATIONAL RELEVANCE: The alpha-RECIST and National Cancer Center strategy are optimal methods for determining therapeutic response to a combination of anti-angiogenic therapy plus immunotherapy and facilitating accurate prognostic stratification for HCC in the AFP ≥ 20 ng/mL group and the whole cohort, which may help oncologists for early identification of responders and progression at 6 weeks and clinical decision-making. KEY POINTS: • RECIST 1.1 is indicated for patients with baseline alpha-fetoprotein (AFP) < 20 ng/mL. • For patients with baseline AFP ≥ 20 ng/mL, integrating RECIST 1.1 and AFP response (alpha-RECIST) may aid in the early identification of survival benefits and progression definition prior to the administration of additional efficacious drugs. • The National Cancer Center strategy is an optimal stratified strategy for determining therapeutic response to a combination of anti-angiogenic therapy and immunotherapy for HCC based on baseline AFP levels.

Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment.

BACKGROUND: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition. METHODS: Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI2 analogue (iloprost, 100 µg/kg/day) for 8 days (n = 8-9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography. RESULTS: SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P < 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P < 0.001), but not circulating PGI2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost. CONCLUSION: Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.

Cardiovascular Toxicity of Angiogenesis Inhibitors Among Patients With Cancer in Taiwan: A Nested Case-Control Study.

BACKGROUND: Research on the cardiovascular toxicity of angiogenesis inhibitors among patients with cancer in Taiwan is lacking. This observational study explored the risk of major adverse cardiovascular events (MACEs) associated with angiogenesis inhibitors in Taiwan. METHODS AND RESULTS: We conducted a nested case-control study using the TCR (Taiwan Cancer Registry) linked with the Taiwan National Insurance Claim Database. We matched every case with 4 controls using risk-set sampling by index date, age, sex, cancer type, and cancer diagnosis date. Conditional logistic regression was used to evaluate the risks of MACEs and different cardiovascular events using propensity score adjustment or matching. Sensitivity analyses were used to evaluate the risks matched by cancer stages or exposure within 1 year. Among a cohort of 284 292 after the exclusion of prevalent cases, the incidences of MACEs among the overall cohort and those exposed to angiogenesis inhibitors were 22.5 and 32.5 events per 1000 person-years, respectively. We matched 17 817 cases with 70 740 controls, with a mean age of 74.9 years, and 56.8% of patients were men. After propensity score adjustment, angiogenesis inhibitors were associated with increased risks of MACEs (odds ratio, 4.56; 95% CI, 1.78-11.59). Significantly increased risks were noted for heart failure hospitalization, myocardial infarction, cerebrovascular accident, and venous thromboembolism, but not for new-onset atrial fibrillation. Similar results were observed after matching by cancer stage or restriction of 1-year exposure. CONCLUSIONS: Angiogenesis inhibitors were associated with increased risks of MACEs among patients with various malignancies in Taiwan but were not associated with new-onset atrial fibrillation.