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Results for “Anti-angiogenic agents”

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PubMed2026

Radiogenomics predicts immune microenvironment heterogeneity and response to combination immunotherapy in hepatocellular carcinoma.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents is the preferred first-line therapy option for patients with advanced hepatocellular carcinoma (HCC), yet only a subset of patients responds, urging the quest for prediction biomarkers. We aimed to integrate genomics with radiology to propose an immune-derived radiogenomics biomarker of response to such combination immunotherapy and evaluate its added value in clinical context. METHODS: We integrated bulk RNA sequencing (RNA-seq) and proteomics data of 994 HCC patients with single-cell RNA-seq data of 11 samples across multiple datasets to identify an immune-related signature (IRS) that may influence sensitivity or resistance to such combined immunotherapy strategy, followed by verification of selected marker genes using immunohistochemistry and cytological experiments. We then trained/validated a cross-modality radiogenomics biomarker using machine learning based on TCIA database that was further tested in multi-scale independent cohorts covering 754 HCC patients. RESULTS: Integrative multi-omics analysis identifed a parsimonious 2-gene prognostic signature including KPNA2 and SMG5 that was significantly associated with immune heterogeneity and response to combination immunotherapy. Machine-learning pipeline exported the optimal 4-feature radiogenomics biomarker using support vector machine that significantly discriminated prognosis (hazard ratio 1.415&#x2013;1.890; p&#x2009;<&#x2009;0.05 for all) and modestly predicted response to ICI plus anti-angiogenic therapy (area under the curve 0.720&#x2013;0.829) in independent retrospective series across major imaging modalities (computed tomography/magnetic resonance imaging). In a prospective neoadjuvant cohort, this biomarker also showed favorable performance for predicting pathological response and tumor recurrence, accompanied by biological validation through single-cell RNA-seq analysis of pre-treatment biopsies. CONCLUSIONS: Our study provides a cross-device-cross-modal radiogenomics biomarker that can improve patient selection for emerging ICI plus anti-angiogenic therapy with novel potential therapeutic targets in HCC.

Humans↗
PubMed2026

Targeting EGFR-Mutant Non-Small Cell Lung Cancer in Asia: An Update on Monotherapy and Combination Therapy&#xa0;With EGFR Inhibitors.

EGFR-mutant lung cancer represents a major subtype of non-small cell lung cancer in Asia, with particularly high prevalence in never-smokers, women, and patients with adenocarcinoma histology. Although this clinicopathologic enrichment has been recognized for more than two decades, the mechanisms underlying the excess frequency of EGFR-mutant disease in Asian populations remain only partially understood. Accumulating evidence suggests a multifactorial basis involving host genetic susceptibility and diversity, endogenous mutational processes and exogenous exposures such as ambient particulate matter. In particular, recent genomic and experimental studies support a tumour-promotion framework in which inflammatory microenvironmental cues may facilitate the outgrowth of pre-existing oncogenic clones, while mutational signatures provide genomic footprints of these processes. In parallel, the treatment landscape for EGFR-mutant non-small cell lung cancer has evolved substantially with successive generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs), leading to marked improvements in survival. However, acquired resistance remains inevitable in most patients with advanced disease and is driven by both genetic and non-genetic mechanisms, including secondary EGFR alterations, bypass pathway activation, TP53-associated genomic instability, adaptive mutagenesis, and drug-tolerant persister states. These insights have provided a strong rationale for combination strategies beyond EGFR-TKI monotherapy. In this review, we summarize current understanding of the epidemiology and biological basis of EGFR-mutant lung cancer in Asia and discuss the preclinical rationale and emerging clinical evidence supporting combination approaches with chemotherapy, anti-angiogenic agents, and EGFR/MET-directed therapies.

EGFR mutations↗
PubMed2026

Beyond the "cold" barrier: Redefining the clinical paradigm of immune checkpoint inhibitor therapy in ovarian cancer.

Ovarian cancer remains an immunologically "cold" tumor, with early all-comer immune checkpoint inhibitor (ICI) trials largely negative despite underlying immunogenicity. This review takes a clinician-centric, stage-specific view linking regimen choice, treatment line, and tumor-immune context to observed outcomes. In the neoadjuvant and first-line settings, unselected ICI combinations with chemotherapy and anti-angiogenic agents failed to improve progression-free survival, whereas adding a poly (ADP-ribose) polymerase (PARP) inhibitor to ICI maintenance yielded modest gains in biomarker-enriched cohorts. In recurrent disease, single-agent ICIs produced objective response rates of 8-15%, and most randomized combinations were negative. The phase III KEYNOTE-B96 trial in platinum-resistant disease demonstrated a progression-free survival benefit in the intention-to-treat population and an overall survival benefit in tumors with programmed death ligand 1 (PD-L1) combined positive score &#x2265;&#x202f;1 when pembrolizumab was paired with weekly paclitaxel with or without bevacizumab, underscoring the value of an immunomodulatory chemotherapy backbone in earlier lines. Ovarian clear cell carcinoma emerges as an immunotherapy-sensitive, chemo-resistant subtype that warrants dedicated stratification. We explain why single-analyte biomarkers-PD-L1, tumor mutational burden, homologous recombination deficiency/BRCA1/2-have not reliably enriched benefit and outline a multidimensional approach integrating genomic scars (e.g., mutational signature 3), immune functional state (Immunoscore, CD8&#x207a; tumor-infiltrating lymphocyte density and CD8&#x207a;: regulatory T-cell ratio), and spatial architecture (inflamed, excluded, desert phenotypes). This framework aims to move beyond the all-comer era toward context-informed precision immunotherapy in ovarian cancer.

Humans↗
PubMed2026

Exploring trop-2-directed ADCs monotherapy and combination therapy in pretreated mTNBC: a real-world study.

PURPOSE: Although Trop-2 antibody-drug conjugates (ADCs) have improved outcomes in pretreated metastatic triple-negative breast cancer (mTNBC), resistance remains common and the optimal combination strategy in routine practice is unclear. METHODS: In this retrospective real-world study, we identified patients with mTNBC from a health record-derived database who received sacituzumab govitecan or sacituzumab tirumotecan in the later-line setting between April 2020 and December 2025. Patients received at least two cycles of Trop-2 ADC therapy as monotherapy, plus a PD-1 inhibitor (dual-agent combination), or plus a PD-1 inhibitor and an antiangiogenic agent (triple-agent combination). RESULTS: Descriptively, the ORR was 57.1% in the triple-agent combination group, 38.5% in the dual-agent combination group, and 31.7% in the monotherapy group. Median follow-up was 15.2 months (95% CI, 8.7-20.6). Median progression-free survival (mPFS) was 15.4 months (95% CI, 5.3-NA) in the triple-agent combination group, 10.0 months (95% CI, 4.2-NA) in the dual-agent combination group, and 3.8 months (95% CI, 3.2-5.2) in the monotherapy group. Severe treatment-related toxicity was not increased in the combination groups. Exploratory analyses identified a genomic scoring system that may enable stratification of patients with a higher likelihood of benefiting from the triple-agent combination. CONCLUSION: To our knowledge, this study represents one of the earliest real-world evaluations of this triple-agent strategy in previously treated mTNBC, providing a basis for further prospective validation and biomarker-guided application.

Humans↗
PubMed1978

Inhibition of lymphocyte-induced angiogenesis by enzymatically isolated rabbit cornea cells.

Corneal and kidney cells were isolated from adult rabbits by enzymatic digestion. The were tested for anti-angiogeneic activity by the lymphocyte-induced angiogenesis assay. In this assay an intradermal injection of semi-allogeneic lymphocytes resulted in a new blood vessel formation visible after three days at the injection site. Isolated rabbit cells were mixed in 1:10 ratio with murine lymphocytes and injected into 600 R X-ray irradiated mice. Number of newly formed blood vessels evoked by lymphocytes injected alone or with rabbit cells added was counted. Corneal cells but not kidney cells decreased angiogenesis evoked by lymphocytes. This finding is discussed in view of corneal avascularity and pathological neo-vascularization.

Angiogenesis Inducing Agents↗
PubMed2026

Discovery of NAT-6-321056 as a novel modulator of VEGFR2 signaling to suppress tumor angiogenesis.

Vascular endothelial growth factor receptor 2 (VEGFR2) is a master regulator of angiogenesis and cancer progression. However, current VEGFR2 modulators face significant challenges, including off-target toxicity and acquired resistance, underscoring the urgent need for novel therapeutic agents with improved efficacy and safety profiles. Here, we reported that virtual screening of 39,442 natural products from the ZINC natural products-derived library, coupled with molecular docking and molecular dynamics (MD) simulations to evaluate the binding stability of candidate compounds, identified NAT-6-321056 as a highly promising modulator of VEGFR2 signaling. Biological evaluations demonstrated that NAT-6-321056 exerted potent inhibition on the growth of a broad spectrum of cancer cells, including both solid tumors and hematological malignancies. In EA.hy 926 endothelial cells and SK-N-DZ neuroblast cells, the compound significantly suppressed proliferation, migration, and invasion. Microscale thermophoresis (MST) confirmed direct binding of NAT-6-321056 to VEGFR2 with favorable affinity. Kinase profiling against a panel of 33 kinases indicated that NAT-6-321056 exhibited a multi-kinase modulation profile. Mechanistic studies revealed that NAT-6-321056 suppressed the expression of hypoxia-inducible factor 1-alpha (HIF-1&#x3b1;) and was associated with reduced VEGFR2 phosphorylation and attenuation of the downstream ERK/JNK/AKT signaling pathways. Moreover, NAT-6-321056 exhibited robust in vivo anti-angiogenic effects in both the chick chorioallantoic membrane (CAM) assay and transgenic zebrafish vascular fluorescence imaging models. Computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction suggested acceptable drug-like properties. Collectively, these findings demonstrated that NAT-6-321056 is a promising modulator of VEGFR2 signaling with potent anti-angiogenic activity and represents a viable candidate for cancer therapy.

Vascular Endothelial Growth Factor Receptor-2↗
PubMed2026

Molecular targeted therapy in combination with chemotherapy for the treatment of platinum-resistant/refractory ovarian cancer (PROC): a systematic review and network meta-analysis.

BACKGROUND: Although single-agent chemotherapy is the most common approach for treating platinum-resistant or refractory ovarian cancer (PROC), there is growing evidence that combining molecular targeted agents with chemotherapy is beneficial, especially for certain patient groups. However, the most effective combination regimen remains elusive. OBJECTIVES: This Bayesian network meta-analysis (NMA) aims to identify the best combination therapy for PROC. METHODS: Relevant studies were searched in PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials from their inception until October 2024. The primary outcomes were overall survival (OS), progression-free survival (PFS) and adverse events (AEs). Statistical analyses were performed using the GEMTC package (1.0-2) and R 4.2.0. This review was registered in PROSPERO (CRD42023428414). RESULTS: Our analysis of 22 randomized controlled trials (RCTs) (n&#xa0;=&#xa0;3408) demonstrated that chemotherapy combinations with bevacizumab (hazard ratio (HR)&#xa0;=&#xa0;0.52-0.65), sorafenib (HR = 0.65, 95% confidence interval (CI): 0.45-0.93) or adavosertib (HR = 0.56, 95%CI: 0.35-0.90) significantly improved OS and PFS versus chemotherapy alone. Notably, adavosertib&#xa0;+&#xa0;gemcitabine was associated with an increased risk of grade 3-4 AEs (relative risk (RR)&#xa0;=&#xa0;1.8, 95%CI: 1.3-2.7), but these were generally manageable. CONCLUSIONS: Bevacizumab-based combinations demonstrate consistent benefits across multiple regimens for PROC. Paclitaxel&#xa0;+&#xa0;bevacizumab emerges as the optimal balance of efficacy and safety. Topotecan&#xa0;+&#xa0;sorafenib could be an alternative for patients who are ineligible for anti-angiogenic therapy.

Humans↗