Thermodynamic consequences of stapling side-chains on a peptide ligand using a lactam-bridge: A theoretical study on anti-angiogenic peptides targeting VEGF.

Peptides are promising therapeutic agents for various biological targets due to their high efficacy and low toxicity, and the design of peptide ligands with high binding affinity to the target of interest is of utmost importance in peptide-based drug design. Introducing a conformational constraint to a flexible peptide ligand using a side-chain lactam-bridge is a convenient and efficient method to improve its binding affinity to the target. However, in general, such a small structural modification to a flexible ligand made with the intent of lowering the configurational entropic penalty for binding may have unintended consequences in different components of the binding enthalpy and entropy, including the configurational entropy component, which are still not clearly understood. Toward probing this, we examine different components of the binding enthalpy and entropy as well as the underlying structure and dynamics, for a side-chain lactam-bridged peptide inhibitor and its flexible analog forming complexes with vascular endothelial growth factor (VEGF), using all-atom molecular dynamics simulations. It is found that introducing a side-chain lactam-bridge constraint into the flexible peptide analog led to a gain in configurational entropy change but losses in solvation entropy, solute internal energy, and solvation energy changes upon binding, pinpointing the opportunities and challenges in drug design. The present study features an interplay between configurational and solvation entropy changes, as well as the one between binding enthalpy and entropy, in ligand-target binding upon imposing a conformational constraint into a flexible ligand.

The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [177Lu]Lu-PSMA-I&T for triple-negative breast cancer.

INTRODUCTION: Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [177Lu]Lu-PSMA-I&T. This study aimed to assess and compare the therapeutic efficacy of a single dose with a fractionated dose of [177Lu]Lu-PSMA-I&T in an orthotopic model of TNBC. METHODS: Rj:NMRI-Foxn1nu/nu mice were used as recipients of MDA-MB-231 xenografts. The single dose group was treated with 1 × 60 ± 5 MBq dose of [177Lu]Lu-PSMA-I&T, while the fractionated dose group received 4 × a 15 ± 2 MBq dose of [177Lu]Lu-PSMA-I&T at 7 day intervals. The control group received 0.9% NaCl. Tumor progression was monitored using [18F]FDG-PET/CT. Ex vivo analysis encompassed immunostaining, TUNEL staining, H&E staining, microautoradiography, and autoradiography. RESULTS: Tumor volumes were significantly smaller in the single dose (p < 0.001) and fractionated dose (p < 0.001) groups. Tumor growth inhibition rates were 38% (single dose) and 30% (fractionated dose). Median survival was notably prolonged in the treated groups compared to the control groups (31d, 28d and 19d for single dose, fractionated dose and control, respectively). [177Lu]Lu-PSMA-I&T decreased the size of viable tumor areas. We further demonstrated, that [177Lu]Lu-PSMA-I&T binds specifically to the tumor-associated vasculature. CONCLUSION: This study highlights the potential of [177Lu]Lu-PSMA-I&T for endogenous radiotherapy of TNBC.

Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism.

Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.

Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. The tumor microenvironment (TME) contributes to the poor response of patients with HCC to current therapies, while tumor vascular endothelial cells (ECs) are fundamental TME components that significantly contribute to tumor progression. However, the specific functions and mechanisms of tumor vascular ECs in HCC remain unclear. METHODS: We screened and validated diacylglycerol kinase gamma (DGKG) hyper-expression specifically in HCC tumor vascular ECs. Single-cell RNA-sequencing, cytometry by time-of-flight, and in vitro and in vivo studies were performed to investigate the functions of endothelial DGKG. Multiplexed immunohistochemistry staining and flow cytometry were used to evaluate changes in the TME. RESULTS: Functionally, endothelial DGKG promotes tumor angiogenesis and immunosuppressive regulatory T-cell differentiation in HCC. Of significance, we found that HIF-1α activates DGKG transcription by directly binding to its promoter region under hypoxia. Upregulated DGKG promotes HCC progression by recruiting ubiquitin specific peptidase 16 to facilitate ZEB2 deubiquitination, which increases TGF-ß1 secretion, thus inducing tumor angiogenesis and regulatory T-cell differentiation. Importantly, targeting endothelial DGKG potentiated the efficiency of dual blockade of PD-1 and VEGFR-2. CONCLUSION: Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immune evasion via the ZEB2/TGF-ß1 axis, suggesting EC-specific DGKG as a potential therapeutic target for HCC. IMPACT AND IMPLICATIONS: Here, we reported that hypoxia-induced endothelial cell-specific DGKG hyper-expression promotes angiogenesis and immune evasion in HCC by recruiting USP16 for K48-linked deubiquitination and inducing the subsequent stabilization of ZEB2, leading to increased TGF-ß1 secretion. Most importantly, endothelial DGKG inhibition greatly improved the efficacy of the dual combination of anti-VEGFR2 and anti-PD-1 treatment in a mouse HCC model, significantly inhibiting the malignant progression of HCC and improving survival. This preclinical study supports the targeting of endothelial DGKG as a potential strategy for precision HCC treatment.

Dual anti-angiogenic and anti-inflammatory action of tRNA-Cys-5-0007 in ocular vascular disease.

BACKGROUND: Intravitreal injections of angiogenesis inhibitors have proved efficacious in the majority of patients with ocular angiogenesis. However, one-fourth of all treated patients fail to derive benefits from intravitreal injections. tRNA-derived small RNA (tsRNA) emerges as a crucial class of non-coding RNA molecules, orchestrating key roles in the progression of human diseases by modulating multiple targets. Through our prior sequencing analyses and bioinformatics predictions, tRNA-Cys-5-0007 has shown as a potential regulator of ocular angiogenesis. This study endeavors to elucidate the precise role of tRNA-Cys-5-0007 in the context of ocular angiogenesis. METHODS: Quantitative reverse transcription PCR (qRT-PCR) assays were employed to detect tRNA-Cys-5-0007expression. EdU assays, sprouting assays, transwell assays, and Matrigel assays were conducted to elucidate the involvement of tRNA-Cys-5-0007 in endothelial angiogenic effects. STZ-induced diabetic model, OIR model, and laser-induced CNV model were utilized to replicate the pivotal features of ocular vascular diseases and evaluate the influence of tRNA-Cys-5-0007 on ocular angiogenesis and inflammatory responses. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were employed to elucidate the anti-angiogenic mechanism of tRNA-Cys-5-0007. Exosomal formulation was employed to enhance the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. RESULTS: tRNA-Cys-5-0007 expression was down-regulated under angiogenic conditions. Conversely, tRNA-Cys-5-0007 overexpression exhibited anti-angiogenic effects in retinal endothelial cells, as evidenced by reduced proliferation, sprouting, migration, and tube formation abilities. In diabetic, laser-induced CNV, and OIR models, tRNA-Cys-5-0007 overexpression led to decreased ocular vessel leakage, inhibited angiogenesis, and reduced ocular inflammation. Mechanistically, these effects were attributed to the targeting of vascular endothelial growth factor A (VEGFA) and TGF-ß1 by tRNA-Cys-5-0007. The utilization of an exosomal formulation further potentiated the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. CONCLUSIONS: Concurrent targeting of tRNA-Cys-5-0007 for anti-angiogenic and anti-inflammatory therapy holds promise for enhancing the effectiveness of current anti-angiogenic therapy.

Translational research on drug development and biomarker discovery for hepatocellular carcinoma.

Translational research plays a key role in drug development and biomarker discovery for hepatocellular carcinoma (HCC). However, unique challenges exist in this field because of the limited availability of human tumor samples from surgery, the lack of homogenous oncogenic driver mutations, and the paucity of adequate experimental models. In this review, we provide insights into these challenges and review recent advancements, with a particular focus on the two main agents currently used as mainstream therapies for HCC: anti-angiogenic agents and immunotherapy. First, we examine the pre-clinical and clinical studies to highlight the challenges of determining the optimal therapeutic combinations with biologically effective dosage for HCC. Second, we discuss biomarker studies focusing on anti-PD1/anti-PD-L1-based combination therapy. Finally, we discuss the progress made in our collective understanding of tumor immunology and in multi-omics analysis technology, which enhance our understanding of the mechanisms underlying immunotherapy, characterize different patient subgroups, and facilitate the development of novel combination approaches to improve treatment efficacy. In summary, this review provides a comprehensive overview of efforts in translational research aiming at advancing our understanding of and improving the treatment of HCC.

A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Systemic therapies and primary tumour downsizing in renal cell carcinoma: a real-world comparison of anti-angiogenic and immune checkpoint inhibition regimens.

PURPOSE: To investigate responses in the primary tumour to different systemic treatment regimens in patients with metastatic renal cell carcinoma (mRCC). METHODS: A single-centre retrospective analysis of treatment-naive mRCC patients without prior nephrectomy receiving VEGF tyrosine kinase inhibitors (VEGF only), immune checkpoint inhibitors (IO only), or combinations thereof (IO + VEGF). The primary outcome was the rate of partial response in the primary tumour (primary tumour PR, ≥ 30% diameter reduction). Secondary outcomes were time to best primary tumour diameter change, overall survival (OS) and progression-free survival (PFS) by Kaplan-Meier analysis. Predictors of survival outcomes were explored by Cox proportional hazards regression analysis. RESULTS: The rate of primary tumour PR was 14% for VEGF only (4/28 patients), 22% for IO only (5/23) and 50% for IO + VEGF (7/14), with median best primary tumour diameter change of - 8.0%, + 5.1%, and - 31.1% respectively, and median time to best primary tumour diameter change of 3.2, 3.0 and 6.9 months respectively. Median OS was significantly greater with IO + VEGF compared to VEGF only (HR 0.45, p = 0.04) and non-significantly greater compared to IO only (HR 0.46, p = 0.06). In multivariable analysis, primary tumour PR was the only response variable significantly associated with both OS (adjusted HR 0.32, p = 0.01) and PFS (adjusted HR 0.29, p < 0.01). CONCLUSION: mRCC patients without prior nephrectomy receiving first-line IO + VEGF regimens showed the greatest primary tumour responses, suggesting further prospective evaluation of this combination in the neoadjuvant and deferred cytoreductive nephrectomy settings.

Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer.

This study aimed to explore advances in biomarkers related to anti-angiogenic therapy in patients with non-small cell lung cancer (NSCLC), thereby enhancing treatment selection, advancing personalized and precision medicine to improve treatment outcomes and patient survival rates. This article reviews key discoveries in predictive biomarkers for anti-angiogenic therapy in NSCLC in recent years, such as (1) liquid biopsy predictive biomarkers: studies have identified activated circulating endothelial cells (aCECs) via liquid biopsy as potential predictive biomarkers for the efficacy of anti-angiogenic therapy; (2) imaging biomarkers: advanced imaging technologies, such as dynamic contrast-enhanced integrated magnetic resonance positron emission tomography (MR-PET), are used to assess tumor angiogenesis in patients with NSCLC and evaluate the clinical efficacy of anti-angiogenic drugs; (3) genetic predictive biomarkers: research has explored polymorphisms of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) and vascular endothelial growth factor-A (VEGF-A), as well as how plasma levels of VEGF-A can predict the outcomes and prognosis of patients with non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. Despite progress in identifying biomarkers related to anti-angiogenic therapy, several challenges remain, including limitations in clinical trials, heterogeneity in NSCLC, and technical hurdles. Future research will require extensive clinical validation and in-depth mechanistic studies to fully exploit the potential of these biomarkers for personalized treatment.

Angiogenic protein profiling, phytochemical screening and in silico anti-cancer targets validation of stem, leaves, fruit, and seeds of Calotropis procera in human liver and breast cancer cell lines.

The main focus of anticancer drug discovery is on developing medications that are gentle on normal cells and should have the ability to target multiple anti-cancer pathways. Liver cancer is becoming a worldwide epidemic due to the highest occurring and reoccurring rate in some countries. Calotropis procera is a xerophytic herbal plant growing wildly in Saudi Arabia. Due to its anti-angiogenic and anticancer capabilities, "C. procera" is a viable option for developing innovative anticancer medicines. However, no study has been done previously, to discover angiogenic and anti-cancer targets which are regulated by C. procera in liver cancer. In this study, leaves, stems, flowers, and seeds of C. procera were used to prepare crude extracts and were fractionated into four solvents of diverse polarities. These bioactivity-guided solvent fractions helped to identify useful compounds with minimal side effects. The phytoconstituents present in the leaves and stem were identified by GC-MS. In silico studies were done to predict the anti-cancer targets by major bioactive constituents present in leaves and stem extracts. A human angiogenesis antibody array was performed to profile novel angiogenic targets. The results from this study showed that C. procera extracts are an ideal anti-cancer remedy with minimum toxicity to normal cells as revealed by zebrafish in vivo toxicity screening assays. The novel antiangiogenic and anticancer targets identified in this study could be explored to design medication against liver cancer.

Antiangiogenic potential of phytochemicals from Clerodendrum inerme (L.) Gaertn investigated through in silico and quantum computational methods.

Suppressing vascular endothelial growth factor (VEGF), its receptor (VEGFR2), and the VEGF/VEGFR2 signaling cascade system to inhibit angiogenesis has emerged as a possible cancer therapeutic target. The present work was designed to discover and evaluate bioactive phytochemicals from the Clerodendrum inerme (L.) Gaertn plant for their anti-angiogenic potential. Molecular docking of twenty-one phytochemicals against the VEGFR-2 (PDB ID: 3VHE) protein was performed, followed by ADMET profiling and molecular docking simulations. These investigations unveiled two hit compounds, cirsimaritin (- 12.29 kcal/mol) and salvigenin (- 12.14 kcal/mol), with the highest binding energy values when compared to the reference drug, Sorafenib (- 15.14 kcal/mol). Furthermore, only nine phytochemicals (cirsimaritin and salvigenin included) obeyed Lipinski's rule of five and passed ADMET filters. Molecular dynamics simulations run over 100 ns revealed that the protein-ligand complexes remained stable with minimal backbone fluctuations. The binding free energy values of cirsimaritin (- 52.35 kcal/mol) and salvigenin (- 55.89 kcal/mol), deciphered by MM-GBSA analyses, further corroborated the docking interactions. The HOMO-LUMO band energy gap (ΔE) was calculated using density-functional theory (DFT) and substantiated using density of state (DOS) spectra. The chemical reactivity analyses revealed that salvigenin exhibited the highest chemical softness value (6.384 eV), the lowest hardness value (0.07831 eV), and the lowest ΔE value (0.1566 eV), which implies salvigenin was less stable and chemically more reactive than cirsimaritin and sorafenib. These findings provide further evidence that cirsimaritin and salvigenin have the ability to prevent angiogenesis and the development of cancer. Nevertheless, more in vitro and in vivo confirmation is necessary.

Morphology of immune-mediated hepatitis: A comparison between immune checkpoint inhibitor therapy and combined immune checkpoint inhibitor/anti-angiogenic therapy.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic drugs has shown promising anticancer effects. However, ICIs can trigger immune-mediated hepatitis (IMH). We aimed to clarify whether the combined use of anti-angiogenic drugs and ICIs would increase the severity of IMH. METHODS: One hundred IMH patients (ICI monotherapy vs. ICI plus anti-angiogenic therapy 30 vs. 70) were retrospectively enrolled. Clinicopathological parameters were compared between the two groups. RESULTS: IMH mainly showed variable degrees of panlobular hepatitis (84 %), while some cases presented mixed cholangio-hepatitic (14 %) or cholangitic (2 %) pattern. The incidence of moderate-severe injury was not significantly different between the two groups (combination vs. monotherapy 38.6 % vs. 20.0 %, p = 0.109). Specifically, the rates of marked lobular injury and portal inflammation were higher in the combination group than in the monotherapy cohort (p < 0.005), while the frequencies of interface hepatitis, bile duct injury, histiocytosis aggregates, and endothelialitis were comparable between the two groups (p > 0.05). Compared to mild IMH cases, severe IMH cases showed higher immunostaining expression levels of PD-L1 (60.7 % vs. 19.4 %, p < 0.0001). Treatments and outcomes of IMH were not significantly different between the two groups (p > 0.05). CONCLUSIONS: Compared to ICI monotherapy, the administration of anti-angiogenic drugs in combination with ICIs was not associated with increased hepatotoxicity.

A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition.

Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.

A 1, 4-benzoquinone derivative isolated from Ardisia crispa (Thunb.) A. DC. root suppresses angiogenesis via its angiogenic signaling cascades.

The root hexane extract of Ardisia crispa (ACRH), which belongs to the Primulaceae family, has been reported to possess anti-inflammatory, chemopreventive, anti-arthritic, and antiangiogenic activities. In this study, we isolated a p-benzoquinone derivative, 2-methoxy-6-undecyl-1,4-benzoquinone (AC2), from ACRH and investigated its potential antiangiogenic activity in human umbilical vein endothelial cells (HUVECs) and zebrafish embryo models. Prior to this study, AC2 was characterized using 1H NMR spectroscopy and MS. AC2 significantly suppressed HUVEC proliferation in a time-independent manner, with an IC50 value of 1.35 ± 0.05, 1.15 ± 0.02, and 1.00 ± 0.01 µg/mL at 24, 48, and 72 h, respectively. AC2 also induced apoptosis in HUVECs and significantly suppressed their migration, invasion, and tube formation in a concentration-dependent manner. Additionally, AC2 significantly attenuated most of the analyzed protein markers, including pro-MMP-2, VEGF-C, VEGF-D, angiopoietin-2, endothelin-1, fibroblast growth factor (FGF)-1, FGF-2, follistatin, heparin-binding epidermal growth factor-like growth factor (HB-EGF), and hepatocyte growth factor (HGF) at all tested concentrations. Furthermore, AC2 significantly inhibited zebrafish embryo intersegmental vessels (ISVs), confirming its antiangiogenic role. In conclusion, AC2 exhibits a potential anti-angiogenic effect by suppressing several proangiogenic and growth factors. Further studies are needed to investigate their effects on other excessive angiogenic diseases.

Effectiveness of PD1/PD-L1 combined with anti-angiogenic drugs in patients with advanced nonsmall cell lung cancer: A systematic review and meta-analysis.

Background: Protein-1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) therapy have become an important treatment approach for patients with advanced nonsmall cell lung cancer (NSCLC), but primary or secondary resistance remains a challenge for some patients. PD-1/PD-L1 combined with anti-angiogenic drugs (AAs) in NSCLC patients have potential synergistic effects, and the survival benefit may vary based on a treatment order. To investigate the efficacy of PD-1/PD-L1 combined with AAs as the treatment for patients with advanced NSCLC. Materials and Methods: We comprehensively searched EMBASE, PubMed, Web of Science, CNKI, VIP, and Wanfang databases from January 2017 to September 2022. The Cochrane risk bias tool evaluated the quality of included randomized clinical trials. Newcastle-Ottawa-Scale score was used to evaluate the quality of retrospective studies. Publication bias was evaluated by funnel plot, Begg's test, and Egger's test. Results: Seventeen articles were finally selected, involving 5182 patients. Meta-analysis results showed that PD1/PD-L1 combined with AAs therapy significantly improved progression-free survival (PFS) (hazard ratio [HR] = 0.61, 95% confidence interval [CI]: 0.50-0.75, P < 0.00001), overall survival (OS) (HR = 0.79, 95% CI: 0.71-0.88, P < 0.00001), and objective response rate (ORR) (risk ratio = 0.88, 95% CI: 0.81-0.96, P = 0.004), with the statistically significant difference. The sensitivity analysis demonstrated the robustness of the PFS, ORR, and OS. Conclusion: The combination of PD-1/PD-L1 inhibitors with AAs in treating advanced patients has exhibited notable therapeutic advantages when contrasted with monotherapy. Specifically, the administration of PD-1/PD-L1 inhibitors in conjunction with AAs, or sequential treatment involving PD-1/PD-L1 followed by AAs, has shown enhanced therapeutic efficacy in this patient population.

[Effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration]. / Effektivnost' i bezopasnost' brolutsizumaba v lechenii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii.

PURPOSE: This study analyzes the effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration (nAMD) in real clinical practice. MATERIAL AND METHODS: The study included patients with nAMD who received brolucizumab treatment and evaluated the changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume, as well as the number of injections and adverse events. RESULT: The group of previously treated patients included 28 subjects (28 eyes) that were switched to brolucizumab with a loading phase. By 12 months, BCVA changed from 0.43±0.29 to 0.33±0.27 LogMAR (p=0.11), CRT decreased from 281.5±58.2 to 239.9±45.6 µm (p=0.02). The group of previously untreated patients included 29 subjects (29 eyes). By 12 months, BCVA changed from 0.47±0.32 to 0.40±0.30 LogMAR (p=0.09), CRT decreased from 333.2±77.3 to 226.2±49.6 µm (p<0.001). Patients received 6.3±0.7 injections. In this group, baseline choroidal thickness showed a statistically significant correlation with final visual acuity (r=0.54; p<0.05) and CRT (r= -0.5; p<0.05). The group of previously treated patients switched without a loading phase included 18 patients (18 eyes). By 6 months, BCVA changed from 0.42±0.2 to 0.37±0.26 LogMAR (p=0.42). CRT remained stable at 285.6±56.9 µm (p=0.97). No adverse events related to intraocular inflammation were reported during the course of 385 injections. CONCLUSION: Brolucizumab therapy helps achieve significant anatomical and functional improvements in real clinical practice both in patients switched from previous treatments and in treatment-naïve patients. Greater baseline choroidal thickness may be associated with better anatomical and functional outcomes with brolucizumab treatment.

Counter regulation of tumor angiogenesis by vascular endothelial growth factor and thrombospondin-1.

Considerable progress has been made in our understanding of the process of angiogenesis in the context of normal and tumor tissue over the last fifty years. Angiogenesis, like most physiological processes, is carefully controlled by dynamic and opposing effects of positive factors, such as vascular endothelial growth factor (VEGF), and negative factors, such as thrombospondin-1. In most cases, the progression of a small mass of cancerous cells to a life-threatening tumor depends upon the initiation of angiogenesis and involves the dysregulation of the angiogenic balance. Whereas our newfound appreciation for the role of angiogenesis in cancer has opened up new avenues for treatment, the success of these treatments, which have focused almost exclusively on antagonizing the VEGF pathway, has been limited to date. It is anticipated that this situation will improve as more therapeutics that target other pathways are developed, more strategies for combination therapies are advanced, more detailed stratification of patient populations occurs, and a better understanding of resistance to anti-angiogenic therapy is gained.

Disrupting cancer angiogenesis and immune checkpoint networks for improved tumor immunity.

Immune checkpoint inhibitors (ICIs) have advanced the field of cancer immunotherapy in patients by sustaining effector immune cell activity within the tumor microenvironment. However, the approach in general is still faced with issues related to ICI response duration/resistance, treatment eligibility, and safety, which indicates a need for further refinements. As immune checkpoint upregulation is inextricably linked to cancer-induced angiogenesis, newer clinical efforts have demonstrated the feasibility of disrupting both tumor-promoting networks to mediate enhanced immune-driven protection. This review focuses on such key evidence stipulating the necessity of co-applying ICI and anti-angiogenic strategies in cancer patients, with particular interest in highlighting newer engineered antibody approaches that may provide theoretically superior multi-pronged and safe therapeutic combinations.

Extracellular vesicles in tumor angiogenesis and resistance to anti-angiogenic therapy.

Tumor angiogenesis plays an important role in the development of cancer as it allows the delivery of oxygen, nutrients, and growth factors as well as tumor dissemination to distant organs. Although anti-angiogenic therapy (AAT) has been approved for treating various advanced cancers, this potential strategy has limited efficacy due to resistance over time. Therefore, there is a critical need to understand how resistance develops. Extracellular vesicles (EVs) are nano-sized membrane-bound phospholipid vesicles produced by cells. A growing body of evidence suggests that tumor cell-derived EVs (T-EVs) directly transfer their cargoes to endothelial cells (ECs) to promote tumor angiogenesis. Importantly, recent studies have reported that T-EVs may play a major role in the development of resistance to AAT. Moreover, studies have demonstrated the role of EVs from non-tumor cells in angiogenesis, although the mechanisms involved are still not completely understood. In this review, we provide a comprehensive description of the role of EVs derived from various cells, including tumor cells and non-tumor cells, in tumor angiogenesis. Moreover, from the perspective of EVs, this review summarized the role of EVs in the resistance to AAT and the mechanisms involved. Due to their role in the resistance of AAT, we here proposed potential strategies to further improve the efficacy of AAT by inhibiting T-EVs.

Low-dose anlotinib confers improved survival in combination with immune checkpoint inhibitor in advanced non-small cell lung cancer patients.

BACKGROUND: Anti-angiogenic drugs increase anti-tumor efficacy of immune checkpoint inhibitors (ICIs). However, the optimal dose of anti-angiogenic drugs remains unclear. METHODS: We retrospectively analyzed efficacy and safety data from patients diagnosed with advanced or metastatic non-small cell lung cancer (NSCLC) that received PD-1 blockade with low-doses of anlotinib, a highly selective receptor tyrosine kinase inhibitor mainly targeting vascular endothelial growth factor receptors, as second or later line therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety profile. Univariate and multivariate analyses were used to identify prognostic factors. RESULTS: A total of 40 eligible patients were included. The median PFS was 11.4 months. The median OS of the entire cohort was 27.0 months. ORR was achieved in 16 patients (40.0%) and DCR was maintained in 33 patients (82.5%). The overall incidence of adverse events (AEs) was 52.5%, and the most common all grade AE was gastrointestinal reactions, which occurred in four patients (10.0%). Treatment-related grade 3/4 toxicity was observed in one patient (2.5%). Conclusions Low-dose anlotinib may be an effective and well-tolerated anti-angiogenesis partner for combination therapy with ICIs in second-line and later settings for advanced NSCLC.