Regulation Of Tumor Angiogenesis Research Articles

Role of Cancer Side Population Stem Cells in Ovarian Cancer Angiogenesis.

Ovarian cancer is one of the most common gynecologic malignancies. Recurrence and metastasis often occur after treatment, and it has the highest mortality rate of all gynecological tumors. Cancer stem cells (CSCs) are a small population of cells with the ability of self-renewal, multidirectional differentiation, and infinite proliferation. They have been shown to play an important role in tumor growth, metastasis, drug resistance, and angiogenesis. Ovarian cancer side population (SP) cells, a type of CSC, have been shown to play roles in tumor formation, colony formation, xenograft tumor formation, ascites formation, and tumor metastasis. The rapid progression of tumor angiogenesis is necessary for tumor growth; however, many of the mechanisms driving this process are unclear as is the contribution of CSCs. The aim of this review was to document the current state of knowledge of the molecular mechanism of ovarian cancer stem cells (OCSCs) in regulating tumor angiogenesis.

Nucleic acid cancer vaccines targeting tumor related angiogenesis. Could mRNA vaccines constitute a game changer?

Tumor related angiogenesis is an attractive target in cancer therapeutic research due to its crucial role in tumor growth, invasion, and metastasis. Different agents were developed aiming to inhibit this process; however they had limited success. Cancer vaccines could be a promising tool in anti-cancer/anti-angiogenic therapy. Cancer vaccines aim to initiate an immune response against cancer cells upon presentation of tumor antigens which hopefully will result in the eradication of disease and prevention of its recurrence by inducing an efficient and long-lasting immune response. Different vaccine constructs have been developed to achieve this and they could include either protein-based or nucleic acid-based vaccines. Nucleic acid vaccines are simple and relatively easy to produce, with high efficiency and safety, thus prompting a high interest in the field. Different DNA vaccines have been developed to target crucial regulators of tumor angiogenesis. Most of them were successful in pre-clinical studies, mostly when used in combination with other therapeutics, but had limited success in the clinic. Apparently, different tumor evasion mechanisms and reduced immunogenicity still limit the potential of these vaccines and there is plenty of room for improvement. Nowadays, mRNA cancer vaccines are making remarkable progress due to improvements in the manufacturing technology and represent a powerful potential alternative. Apart from their efficiency, mRNA vaccines are simple and cheap to produce, can encompass multiple targets simultaneously, and can be quickly transferred from bench to bedside. mRNA vaccines have already accomplished amazing results in cancer clinical trials, thus ensuring a bright future in the field, although no anti-angiogenic mRNA vaccines have been described yet. This review aims to describe recent advances in anti-angiogenic DNA vaccine therapy and to provide perspectives for use of revolutionary approaches such are mRNA vaccines for anti-angiogenic treatments.

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.

N-myc downstream–regulated gene 1 can promote vasculogenic mimicry and angiogenesis in urothelial carcinoma

Urothelial carcinoma (UC) of the bladder is a common cause of cancer-related death worldwide. Vasculogenic mimicry (VM) is a process by which the malignant cells can generate vascular-like structures formed of periodic acid–Schiff (PAS) positive/CD31 negative extracellular matrix independent of angiogenesis and thus promotes tumor progression. N-myc downstream–regulated gene 1 (NDRG1) is a protein that can modulate tumor angiogenesis; however, its role in regulating tumor angiogenesis and VM formation has not been previously investigated in UC. This study aims to evaluate the role of intra-tumor microvessel density (MVD) (as a surrogate measure of angiogenesis), VM, and NDRG1 in UC and their correlation with different clinicopathologic features, then assess the correlation between them in UC. Sixty specimens of UC of the bladder were included. PAS-CD31 immunohistochemical double staining method was used to evaluate the intra-tumor MVD and VM. Immunohistochemical expression of NDRG1 was also examined. VM and NDRG1 expression were detected in 41.7% and 83.3% of UC specimens respectively. The mean of intra-tumor MVD, VM area, and NDRG1 was significantly higher in tumors with higher grade, lymphovascular invasion, and higher T stage. NDRG1 expression was positively correlated with MVD and VM. We can suggest that MVD, VM, and NDRG1 may serve as poor prognostic markers for UC. The positive correlation between NDRG1 and both MVD and VM may provide the first evidence that NDRG1 can induce tumor angiogenesis and VM in UC which may offer a novel pathway for further therapeutic strategies.

Diterpenoid tanshinones inhibit gastric cancer angiogenesis through the PI3K/Akt/mTOR signaling pathway

Ethnopharmacological relevanceSalvia miltiorrhiza Bunge is a kind of Chinese herbal medicine known for activating blood circulation and removing blood stasis, with the effect of cooling blood and eliminating carbuncles, and has been proven to have the effect of treating tumors. However, the inhibitory effect of Salvia miltiorrhiza Bunge extracts (Diterpenoid tanshinones) on tumors by inhibiting angiogenesis has not been studied in detail. Aim of the studyThis study aimed to investigate the anti-gastric cancer effect of diterpenoid tanshinones (DT) on angiogenesis, including the therapeutic effects and pathways. Materials and methodsThis experiment utilized network pharmacology was used to identify relevant targets and pathways of Salvia miltiorrhiza Bunge-related components in the treatment of gastric cancer. The effects of DT on the proliferation and migration of human gastric cancer cell line SGC-7901 and human umbilical vein endothelial cell line HUVECs were evaluated, and changes in the expression of angiogenesis-related factors were measured. In vivo, experiments were conducted on nude mice to determine tumor activity, size, immunohistochemistry, and related proteins. ResultsThe findings showed that DT could inhibit the development of gastric cancer by suppressing the proliferation of gastric cancer cells, inducing apoptosis, and inhibiting invasion and metastasis. In addition, the content of angiogenesis-related factors and proteins was significantly altered in DT-affected cells and animals. ConclusionsResults suggest that DT has potential as a therapeutic agent for the treatment of gastric cancer, as it can inhibit tumor growth and angiogenesis. It was also found that DT may affect the expression of the angiogenic factor VEGF through the PI3K/Akt/mTOR pathway, leading to the regulation of tumor angiogenesis. This study provides a new approach to the development of anti-tumor agents and has significant theoretical and clinical implications for the treatment of gastric cancer.

Identification and validation of anoikis-related lncRNAs for prognostic significance and immune microenvironment characterization in ovarian cancer.

Anoikis, a form of apoptotic cell death resulting from inadequate cell-matrix interactions, has been implicated in tumor progression by regulating tumor angiogenesis and metastasis. However, the potential roles of anoikis-related long non-coding RNAs (arlncRNAs) in the tumor microenvironment are not well understood. In this study, five candidate lncRNAs were screened through least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis based on differentially expressed lncRNAs associated with anoikis-related genes (ARGs) from TCGA and GSE40595 datasets. The prognostic accuracy of the risk model was evaluated using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) analyses revealed significant differences in immune-related hallmarks and signal transduction pathways between the high-risk and low-risk groups. Additionally, immune infiltrate analysis showed significant differences in the distribution of macrophages M2, follicular T helper cells, plasma cells, and neutrophils between the two risk groups. Lastly, silencing the expression of PRR34_AS1 and SPAG5_AS1 significantly increased anoikis-induced cell death in ovarian cancer cells. In conclusion, our study constructed a risk model that can predict clinicopathological features, tumor microenvironment characteristics, and prognosis of ovarian cancer patients. The immune-related pathways identified in this study may offer new treatment strategies for ovarian cancer.

Assessing angiogenesis factors as prognostic biomarkers in breast cancer patients and their association with clinicopathological factors

Introduction Angiogenesis is fundamental for tumor growth and metastasis across many solid malignancies. Considerable interest has focused on the molecular regulation of tumor angiogenesis as a means to predict disease outcomes and guide therapeutic decisions. Methods In the present study, we investigated the prognostic value of transforming growth factor beta (TGF-β), epidermal growth factor (EGF), fibroblast growth factor (FGF), delta-like ligand 4 (DLL4), and vascular endothelial growth factor (VEGF) in the serum of 120 women diagnosed with breast cancer using ELISA as well as examined their associations with clinical parameters and the outcome of the disease. Results Our results demonstrated that the serum concentration of TGF-β and EGF were remarkably higher in patients with higher tumor size, end stages of the disease, and positive lymph node involvement compared to patients with lower tumor size, early stages of the disease, and negative lymph node involvement. In addition, we found a significant correlation between the serum concentration of VEGF and the level of EGF, FGF, and DLL4 in patients with breast cancer. Furthermore, both univariate and multivariate analyses showed that TGF-β and EGF can be used as end-stage predictors. Discussion/Conclusion Based on our findings, increasing the level of angiogenesis factors is significantly associated with higher tumor size and late stages of the disease in patients with breast cancer. Moreover, measuring the level of angiogenesis factors could lead to better prediction of disease outcomes and choosing the best treatments for patients.

Regulation of Angiogenesis by Non-Coding RNAs in Cancer.

Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been identified as crucial regulators of various biological processes through epigenetic regulation, transcriptional regulation, and post-transcriptional regulation. Growing evidence suggests that dysregulation and activation of non-coding RNAs are closely associated with tumor angiogenesis, a process essential for tumor growth and metastasis and a major contributor to cancer-related mortality. Therefore, understanding the molecular mechanisms underlying tumor angiogenesis is of utmost importance. Numerous studies have documented the involvement of different types of non-coding RNAs in the regulation of angiogenesis. This review provides an overview of how non-coding RNAs regulate tumor angiogenesis. Additionally, we discuss emerging strategies that exploit non-coding RNAs for anti-angiogenic therapy in cancer treatment. Ultimately, this review underscores the crucial role played by non-coding RNAs in tumor angiogenesis and highlights their potential as therapeutic targets for anti-angiogenic interventions against cancer.

Hypoxia-induced TMTC3 expression in esophageal squamous cell carcinoma potentiates tumor angiogenesis through Rho GTPase/STAT3/VEGFA pathway

BackgroundHypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key transcription factor regulator to promote tumor angiogenesis in the adaptive response to hypoxia. Increasing evidence has suggested that hypoxia plays an important regulatory role of ER homeostasis. We previously identified TMTC3 as an ER stress mediator under nutrient-deficiency condition in esophageal squamous cell carcinoma (ESCC), but the molecular mechanism in hypoxia is still unclear.MethodsRNA sequencing data of TMTC3 knockdown cells and TCGA database were analyzed to determine the association of TMTC3 and hypoxia. Moreover, ChIP assay and dual-luciferase reporter assay were performed to detect the interaction of HIF-1α and TMTC3 promoter. In vitro and in vivo assays were used to investigate the function of TMTC3 in tumor angiogenesis. The molecular mechanism was determined using co-immunoprecipitation assays, immunofluorescence assays and western blot. The TMTC3 inhibitor was identified by high-throughput screening of FDA-approved drugs. The combination of TMTC3 inhibitor and cisplatin was conducted to confirm the efficiency in vitro and in vivo.ResultsThe expression of TMTC3 was remarkably increased under hypoxia and regulated by HIF-1α. Knockdown of TMTC3 inhibited the capability of tumor angiogenesis and ROS production in ESCC. Mechanistically, TMTC3 promoted the production of GTP through interacting with IMPDH2 Bateman domain. The activity of Rho GTPase/STAT3, regulated by cellular GTP levels, decreased in TMTC3 knockdown cells, whereas reversed by IMPDH2 overexpression. Additionally, TMTC3 regulated the expression of VEGFA through Rho GTPase/STAT3 pathway. Allopurinol inhibited the expression of TMTC3 and further reduced the phosphorylation and activation of STAT3 signaling pathway in a dose-dependent manner in ESCC. Additionally, the combination of allopurinol and cisplatin significantly inhibited the cell viability in vitro and tumor growth in vivo, comparing with single drug treatment, respectively.ConclusionsCollectively, our study clarified the molecular mechanism of TMTC3 in regulating tumor angiogenesis and highlighted the potential therapeutic combination of TMTC3 inhibitor and cisplatin, which proposed a promising strategy for the treatment of ESCC.

Angiopoietin4 (ANGPT4) expression and potential mechanisms in carcinogenesis: current achievements and perspectives.

Angiopoietin4(ANGPT4) which plays a significant role in endothelial cell proliferation, survival, angiogenesis and expansion in tumors and other pathological states is a significant regulator of tumor angiogenesis. ANGPT4 expression is enhanced in many cancer cells. For example, the overexpression of ANGPT4 promotes the formation, development and progress of lung adenocarcinoma, glioblastoma and ovarian cancer. Related studies show that ANGPT4 encourages the proliferation, survival and invasion of tumor cells, while promoting the expansion of the tumor vascular system and affecting the tumor immune microenvironment. ANGPT4 can also promote carcinogenesis by affecting the ERK1/2, PI3K/AKT and other signal pathways downstream of tyrosine kinase with immunoglobulin-like and EGF-like domains 2(TIE2) and TIE2. Therefore, ANGPT4 may be a potential and significant biomarker for predicting malignant tumor progression and adverse outcomes. In addition, inhibition of ANGPT4 may be a meaningful cancer treatment. This paper reviews the latest research results of ANGPT4 in preclinical research, and emphasizes its role in carcinogenesis. Additional research on the carcinogenic function of ANGPT4 could provide new insights into cancer biology and novel methods for cancer diagnosis and treatment.

Beta IV spectrin inhibits the metastatic growth of melanoma by suppressing VEGFR2-driven tumor angiogenesis.

Tumor-associated angiogenesis mediates the growth and metastasis of most solid cancers. Targeted therapies of the VEGF pathways can effectively block these processes but often fail to provide lasting benefits due to acquired resistance and complications. Recently, we discovered βIV -spectrin as a powerful regulator of angiogenesis and potential new target. We previously reported that βIV -spectrin is dynamically expressed in endothelial cells (EC) to induce VEGFR2 protein turnover during development. Here, we explored how βIV -spectrin influences the tumor vasculature using the murine B16 melanoma model and determined that loss of EC-specific βIV -spectrin dramatically promotes tumor growth and metastasis. Intraperitoneally injected B16 cells formed larger tumors with increased tumor vessel density and greater propensity for metastatic spread particularly to the chest cavity and lung compared to control mice. These results support βIV -spectrin as a key regulator of tumor angiogenesis and a viable vascular target in cancer.

In Silico and In Vitro Evaluation of Bevacizumab Biosimilar MB02 as an Antitumor Agent in Canine Mammary Carcinoma.

Canine mammary carcinomas (CMC) are associated with major aggressive clinical behavior and high mortality. The current standard of care is based on surgical resection, without an established effective treatment scheme, highlighting the urgent need to develop novel effective therapies. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis and progression in the majority of solid cancers, including human and canine mammary carcinomas. The first therapy developed to target VEGF was bevacizumab, a recombinant humanized monoclonal antibody, which has already been approved as an anticancer agent in several human cancers. The goal of this work was to establish the therapeutic value of MB02 bevacizumab biosimilar in CMC. First, through different in silico approaches using the MUSCLE multiple-sequence alignment tool and the FoldX protein design algorithm, we were able to predict that canine VEGF is recognized by bevacizumab, after showing an extremely high sequence similarity between canine and human VEGF. Further, by using an ELISA-based in vitro binding assay, we confirmed that MB02 biosimilar was able to recognize canine VEGF. Additionally, canine VEGF-induced microvascular endothelial cell proliferation was inhibited in a concentration-dependent manner by MB02 biosimilar. These encouraging results show a high potential for MB02 as a promising therapeutic agent for the management of CMC.

Neutrophils regulate tumor angiogenesis in oral squamous cell carcinoma and the role of Chemerin.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity. Tumor angiogenesis plays a crucial role in tumor progression. Studies have established the correlation between neutrophils and tumor angiogenesis in the tumor microenvironment. A previous study found that overexpression of Chemerin- in OSCC increased the infiltration of neutrophils in tumor tissues. This study aims to investigate the mechanisms underlying the regulation of the development and progression of OSCC, which have great significance in enhancing the postoperative survival of patients with OSCC. This study evaluated the accuracy of neutrophil count combined with MVD in predicting patients' survival time and its relationship with clinicopathological parameters and prognosis. Additionally, the study explored the effects of the Chemerin-neutrophil interaction on the angiogenic function of HUVECs. In OSCC, the overexpression of Chemerin promoted the angiogenesis of HUVECs through neutrophils. Moreover, Chemerin upregulated pro-angiogenic factors (e.g., VEGF-A, MMP-9, MMP-2, and S100A9) in neutrophils by activating MEK/ERK signaling pathway. In vivo experiments demonstrated that Chemerin may promote tumor growth by regulating tumor angiogenesis. In conclusion, the results suggest that neutrophil count and MVD serve as poor prognostic factors for patients with OSCC, and their combination is a more effective factor in predicting the survival time of OSCC patients. Neutrophils potentially contribute to angiogenesis through MEK/ERK signaling pathway via Chemerin and participate in the progression and metastasis of OSCC.

The Progress of Platelets in Breast Cancer.

Breast cancer is the most common female cancer and the sixth leading cause of death, seriously affecting the quality of life of women. Platelets, one of the fragments derived from megakaryocytes, are being increasingly investigated by tumor researchers because of their anticoagulant function. According to relevant studies, platelets, as the key source of circulating angiogenesis-related factors, can regulate tumor angiogenesis and vascular integrity, and they can also affect the tumor microenvironment, thereby facilitating the proliferation and differentiation of tumor cells. By covering or transferring normal MHC I molecules to tumor cells, platelets can protect tumor cells from being killed by the immune system and facilitate tumor cell metastasis. However, details on the mechanisms involved have remained elusive. This paper reviews and analyzes studies of the role of platelets in tumorigenesis, tumor cell proliferation, tumor metastasis, and cancer treatment to provide readers with a better understanding of the relevant studies.

The functional network of biglycan: A new frontier in tumor progression

AbstractBiglycan is a member of the small leucine‐rich proteoglycan family. Dysregulation of biglycan leads to a broad range of clinical consequences, such as osteoclastogenesis, inflammation, cardiovascular disease, and cancer. Biglycan binding to toll‐like receptor (TLR)−2 or TLR‐4 on immune cells lead to infiltration of immune cells to mediate the inflammatory response. Additionally, the extracellular matrix‐secreted soluble biglycan functions as a danger‐associated molecular pattern molecule involved in the induction of inflammation and cancer. High expression of biglycan is demonstrated in tumor endothelial cells (TECs) of various cancers and correlates with metastatic potential and poor clinical outcomes. This comprehensive review addresses the role of biglycan in both tumor cells and tumor stromal cells, especially TECs, in regulating tumor angiogenesis, tumor growth, metastasis, and chemotherapy resistance.

Regulation of tumor angiogenesis by the crosstalk between innate immunity and endothelial cells.

Endothelial cells and immune cells are major regulators of cancer progression and prognosis. Endothelial cell proliferation and angiogenesis are required for providing nutrients and oxygen to the nascent tumor and infiltration of immune cells to the tumor is dependent on endothelial cell activation. Myeloid cells and innate lymphocytes have an important role in shaping the tumor microenvironment by crosstalking with cancer cells and structural cells, including endothelial cells. Innate immune cells can modulate the activation and functions of tumor endothelial cells, and, in turn, endothelial cell expression of adhesion molecules can affect immune cell extravasation. However, the mechanisms underlying this bidirectional crosstalk are not fully understood. In this review, we will provide an overview of the current knowledge on the pathways regulating the crosstalk between innate immune cells and endothelial cells during tumor progression and discuss their potential contribution to the development of novel anti-tumor therapeutic approaches.

Comparative biochemical kinase activity analysis identifies rivoceranib as a highly selective VEGFR2 inhibitor

Vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis, is highly expressed across numerous tumor types and has been an attractive target for anti-cancer therapy. However, clinical application of available VEGFR2 inhibitors has been challenged by limited efficacy and a wide range of side effects, potentially due to inadequate selectivity for VEGFR2. Thus, development of potent VEGFR2 inhibitors with improved selectivity is needed. Rivoceranib is an orally administered tyrosine kinase inhibitor that potently and selectively targets VEGFR2. A comparative understanding of the potency and selectivity of rivoceranib and approved inhibitors of VEGFR2 is valuable to inform rationale for therapy selection in the clinic. Here, we performed biochemical analyses of the kinase activity of VEGFR2 and of a panel of 270 kinases to compare rivoceranib to 10 FDA-approved kinase inhibitors (“reference inhibitors”) with known activity against VEGFR2. Rivoceranib demonstrated potency within the range of the reference inhibitors, with a VEGFR2 kinase inhibition IC50 value of 16 nM. However, analysis of residual kinase activity of the panel of 270 kinases showed that rivoceranib displayed greater selectivity for VEGFR2 compared with the reference inhibitors. Differences in selectivity among compounds within the observed range of potency of VEGFR2 kinase inhibition are clinically relevant, as toxicities associated with available VEGFR2 inhibitors are thought to be partly due to their effects against kinases other than VEGFR2. Together, this comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with off-target effects of currently available VEGFR2 inhibitors.

VEGF-A165 is the predominant VEGF-A isoform in platelets, while VEGF-A121 is abundant in serum and plasma from healthy individuals.

Vascular endothelial growth factor A (VEGF-A) plays pivotal roles in regulating tumor angiogenesis as well as physiological vascular function. The major VEGF-A isoforms, VEGF-A121 and VEGF-A165, in serum, plasma, and platelets have not been exactly evaluated due to the lack of the appropriate assay system. Antibodies against human VEGF-A121 and VEGF-A165 (hVEGF-A121 and hVEGF-A165) were successfully produced and Enzyme-Linked ImmunoSorbent Assay (ELISA) for hVEGF-A121 and hVEGF-A165 were separately created by these monoclonal antibodies. The measurement of recombinant hVEGF-A121 and hVEGF-A165 by the created ELISA showed no cross-reaction between hVEGF-A121 and hVEGF-A165 in conditioned media from HEK293 cells transfected with either hVEGF-A121 or hVEGF-A165 expression vector. The levels of VEGF-A121 and VEGF-A165 in serum, plasma, and platelets from 59 healthy volunteers proved that VEGF-A121 level was higher than VEGF-A165 in both plasma and serum in all the cases. VEGF-A121 or VEGF-A165 in serum represented higher level than that in plasma. In contrast, the level of VEGF-A165 was higher than VEGF-A121 in platelets. The newly developed ELISAs for hVEGF-A121 and hVEGF-A165 revealed different ratios of VEGF isoforms in serum, plasma, and platelets. Measuring these isoforms in combination provides useful information as biomarkers for diseases involving VEGF-A121 and VEGF-A165.

Dissecting the roles and clinical potential of YY1 in the tumor microenvironment.

Yin-Yang 1 (YY1) is a member of the GLI-Kruppel family of zinc finger proteins and plays a vital dual biological role in cancer as an oncogene or a tumor suppressor during tumorigenesis and tumor progression. The tumor microenvironment (TME) is identified as the "soil" of tumor that has a critical role in both tumor growth and metastasis. Many studies have found that YY1 is closely related to the remodeling and regulation of the TME. Herein, we reviewed the expression pattern of YY1 in tumors and summarized the function and mechanism of YY1 in regulating tumor angiogenesis, immune and metabolism. In addition, we discussed the potential value of YY1 in tumor diagnosis and treatment and provided a novel molecular strategy for the clinical diagnosis and treatment of tumors.

Abstract 4014: Comparative biochemical kinase activity analysis identifies rivoceranib as the most selective VEGFR-2 inhibitor compared with other TKIs with known activity against VEGFR-2

Abstract Introduction: Vascular endothelial growth factor receptor 2 (VEGFR-2) is a key regulator of tumor angiogenesis that is highly expressed in several tumor types and is a known target for anti-cancer therapy. Yet the clinical use of VEGFR-2 inhibitors has been challenged by limited efficacy and various side effects, potentially due to the low selectivity of these TKIs for VEGFR-2. Thus, potent VEGFR-2 inhibitors with improved selectivity are needed. Rivoceranib is an oral tyrosine kinase inhibitor (TKI) that potently and selectively inhibits VEGFR-2. A comparison of the potency and selectivity of VEGFR-2 inhibitors can provide a rationale for selecting a specific TKI for anticancer therapy in the clinic. Methods: Binding of rivoceranib to VEGFR-2 was determined on a Biacore T200. The affinity constant (KD) was derived from the association and dissociation rate constants. Inhibitory potency of rivoceranib and 10 FDA-approved reference inhibitors on kinase enzyme activity was determined using mobility shift assays (MSA) or immobilized metal ion affinity particle (IMAP) assays. The half-maximum inhibitory activity (IC50) of the 11 inhibitors on VEGFR-2 was determined in 10-point dose-response curves. The selectivity of the inhibitors was determined on 270 wild-type kinases at a fixed concentration of each inhibitor. Rivoceranib was tested at 10- and 100-times IC50 (160 nmol/L and 1.6 µmol/L). Reference inhibitors were tested at 1 µmol/L (35 to 1056-times IC50). Results: Rivoceranib had a KD of 3 nmol/L on VEGFR-2. In enzyme activity assays, rivoceranib had intermediate potency compared with the 10 reference inhibitors, with a VEGFR-2 kinase inhibition IC50 value of 16 nmol/L. Analysis of the residual activity of the panel of 270 kinases in the presence of rivoceranib or the reference inhibitors showed wide variation in selectivity for VEGFR-2, with rivoceranib identified as the most selective inhibitor (activity of 16 additional kinases inhibited by >50% at 1.6 µmol/L). Tivozanib, the most potent VEGFR-2 inhibitor, displayed greater than 50% inhibitory activity against more than 70 additional kinases. Sunitinib was identified as the least selective inhibitor included in this study, inhibiting 125 additional kinases by >50%. Conclusion: Variations in selectivity among TKIs with similar anti-VEGFR-2 potency can help explain differences in their clinical toxicity profiles, which may be partially due to variant inhibitory effects against TKIs other than VEGFR-2. This comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with the poor selectivity of currently available VEGFR-2 inhibitors. Rivoceranib is under ongoing investigation as monotherapy and in combination with chemotherapy in various tumor types. Citation Format: Seong Jang, Bill Strickland, Lynda Finis, Jeffrey J. Koojiman, Janneke J. Melis, Guido J. Zaman, Jan V. Tornout. Comparative biochemical kinase activity analysis identifies rivoceranib as the most selective VEGFR-2 inhibitor compared with other TKIs with known activity against VEGFR-2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4014.