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Drug Design, Development and Therapy 2021Neovascular age-related macular degeneration (nAMD) treatment has been revolutionized by the introduction of vascular endothelial growth factor antagonists (anti-VEGF),... (Review)
Review
Neovascular age-related macular degeneration (nAMD) treatment has been revolutionized by the introduction of vascular endothelial growth factor antagonists (anti-VEGF), but the need for frequent intravitreal injections poses a heavy burden to patients and physicians. Evolving anti-VEGF therapies include longer duration agents, approaches that target multiple pathways, topical anti-VEGF agents, sustained-release, and genetic therapies. Abicipar pegol, a designed ankyrin repeat protein (DARPin), demonstrated the ability to maintain stable visual acuity with 12-week dosing, but was not approved by the FDA due to higher than usual rates of intraocular inflammation. Conbercept, a recombinant anti-VEGF fusion protein, has been approved in China, and is in Phase 3 trials globally. KSI-301 is an anti-VEGF antibody biopolymer conjugate that allowed 66% of nAMD patients to maintain at least a 6-month treatment-free interval in Phase 1b studies. OPT-302, an inhibitor of VEGF-C/D, will be tested in phase 3 studies that compare anti-VEGF-A monotherapy against combination therapy with OPT-302. Faricimab is a bispecific anti-VEGF/Ang-2 antibody that upregulates the Tie-2 signaling pathway and promotes vascular stability; it is undergoing phase 3 trials with potential for 12- or 16-week dosing. PAN-90806 is a topical anti-VEGF agent that showed the ability to reduce injection frequency by 79% compared to ranibizumab monotherapy in a phase 1/2a trial. Sustained-release anti-VEGF therapies include the ranibizumab Port Delivery System (in phase 3 studies), GB-102 (Phase 2b), OTX-TKI (phase 1), and Durasert (preclinical). Suprachoroidal delivery of the tyrosine kinase inhibitor, axitinib, is in preclinical studies. Genetic therapies in phase 1 studies include RGX-314 and ADVM-022, which introduce a viral vector that modifies the retina's cellular apparatus to create an anti-VEGF biofactory, potentially serving as a one-time treatment. Further investigation is warranted for drugs and delivery systems that hope to advance visual outcomes and reduce treatment burden of nAMD.
Topics: Angiogenesis Inhibitors; Drug Delivery Systems; Drug Development; Humans; Vascular Endothelial Growth Factor A; Visual Acuity; Wet Macular Degeneration
PubMed: 34188445
DOI: 10.2147/DDDT.S295223 -
Archives of Biochemistry and Biophysics Apr 2011Because angiogenesis underlies the pathogenesis of numerous conditions (cancer, psoriasis, macular degeneration), there is a pressing need for continued investigations... (Review)
Review
Because angiogenesis underlies the pathogenesis of numerous conditions (cancer, psoriasis, macular degeneration), there is a pressing need for continued investigations into angiogenic signaling and potential drug targets. Antiangiogenic agents can be classified as either direct or indirect. Direct antiangiogenics act on untransformed endothelial cells to prevent differentiation and proliferation; indirect antiangiogenics act to inhibit factors involved in proangiogenic signaling. Agents currently available with dermatologic indications are few; while several established and novel biologics targeting various proangiogenic factors are currently being investigated for potential dermatologic uses, but the jury is still out on their efficacy and safety. In this review, we highlight our experience with a group of existing and novel, small molecules that combine several modes of action against angiogenesis in addition to other properties--triarylmethane dyes and fulvene derivatives.
Topics: Angiogenesis Inhibitors; Animals; Coloring Agents; Dermatology; Humans; Methane
PubMed: 21172300
DOI: 10.1016/j.abb.2010.12.016 -
Clinical Colorectal Cancer Sep 2021Combination therapy comprised of fluoropyrimidine plus irinotecan with an angiogenesis inhibitor is widely used as a second-line treatment for metastatic colorectal...
BACKGROUND
Combination therapy comprised of fluoropyrimidine plus irinotecan with an angiogenesis inhibitor is widely used as a second-line treatment for metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS
This retrospective study evaluated the efficacy and safety of fluorouracil and irinotecan (FOLFIRI) plus ramucirumab (RAM); FOLFIRI plus aflibercept (AFL); irinotecan and S-1 (IRIS) plus bevacizumab (BEV); and capecitabine and irinotecan (CAPIRI) plus BEV, with FOLFIRI plus BEV serving as the control among mCRC patients who failed treatment with fluoropyrimidine and oxaliplatin plus BEV. Data were collected from a medical claim database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The primary outcome was time to treatment failure (TTF). Secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and safety.
RESULTS
Among 3,136 patients assessed, TTF was significantly shorter with FOLFIRI plus RAM (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26-1.56; P < .001) and FOLFIRI plus AFL (HR, 1.34; 95% CI, 1.09-1.66; P = .002), and significantly longer with IRIS plus BEV (HR, 0.80; 95% CI, 0.70-0.92; P = .002). TFST was significantly shorter with FOLFIRI plus RAM (HR, 1.32; 95% CI, 1.17-1.49; P < .001); no significant difference in OS was observed. The incidences of neutropenia requiring granulocyte colony-stimulating factor were significantly lower with IRIS plus BEV and CAPIRI plus BEV.
CONCLUSION
Regarding TTF, BEV seemed to be a favorable option compared with RAM and AFL when combined with FOLFIRI, and IRIS might be preferable compared to FOLFIRI when combined with BEV for patients who failed to respond to fluoropyrimidine, oxaliplatin, and BEV.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Retrospective Studies
PubMed: 33875364
DOI: 10.1016/j.clcc.2021.03.001 -
Gynecologic Oncology Mar 2023Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial...
OBJECTIVE
Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts.
METHODS
mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial.
RESULTS
The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment.
CONCLUSIONS
Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials.
Topics: Humans; Female; Bevacizumab; Vascular Endothelial Growth Factor A; Angiogenesis Inhibitors; Retrospective Studies; Prospective Studies; Ovarian Neoplasms; Neovascularization, Pathologic; Prognosis
PubMed: 36758419
DOI: 10.1016/j.ygyno.2023.01.034 -
Expert Review of Gastroenterology &... Aug 2016Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in... (Review)
Review
INTRODUCTION
Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in vitro and in vivo models.
AREAS COVERED
Apatinib's efficacy, tolerability and safety have been evaluated in one Phase II and one Phase III study in metastatic/advanced gastric cancer. In this review, we focus on the mechanism of action of apatinib, its pharmacokinetic profile and its clinical activity in the treatment of advanced/metastatic gastric cancer. Expert commentary: Unfortunately, as yet, there is no definitive biomarker data for apatinib in gastric cancer.
Topics: Angiogenesis Inhibitors; Animals; Humans; Molecular Targeted Therapy; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyridines; Signal Transduction; Stomach Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2
PubMed: 27376400
DOI: 10.1080/17474124.2016.1209407 -
International Journal of Molecular... Aug 2023Neovascular age-related macular degeneration (nAMD) is the primary disastrous retinal disease that leads to blindness in the elderly population. In the early 2000s, nAMD... (Review)
Review
Neovascular age-related macular degeneration (nAMD) is the primary disastrous retinal disease that leads to blindness in the elderly population. In the early 2000s, nAMD resulted in irreversible vision loss and blindness with no available treatment options. However, there have been breakthrough advances in the drug development of anti-angiogenic biological agents over the last two decades. The primary target molecule for treating nAMD is the vascular endothelial growth factor (VEGF), and there are currently several anti-VEGF drugs such as bevacizumab, ranibizumab, and aflibercept, which have made nAMD more manageable than before, thus preventing vision loss. Nevertheless, it should be noted that these anti-VEGF drugs for nAMD treatment are not effective in more than half of the patients, and even those who initially gain visual improvements lose their vision over time, along with potential deterioration in the geography of atrophy. As a result, there have been continuous endeavors to improve anti-VEGF agents through better efficacy, fewer doses, expanded intervals, and additional targets. This review describes past and current anti-VEGF therapeutics used to treat nAMD and outlines future directions to improve the effectiveness and safety of anti-VEGF agents.
Topics: Humans; Aged; Vascular Endothelial Growth Factors; Bevacizumab; Blindness; Angiogenesis Inhibitors; Macular Degeneration
PubMed: 37629185
DOI: 10.3390/ijms241613004 -
Scientific Reports Aug 2022Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor...
Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor progression. However, the benefits are transient, and most patients who initially respond to these therapies develop resistance. Accordingly, there is a need for new anti-angiogenesis therapeutics to delay the processes of resistance or eliminate the resistive effects entirely. This manuscript presents the results of a screen of the National Institutes of Health Clinical Collections Libraries I & II (NIHCCLI&II) for novel angiogenesis inhibitors. The 727 compounds of the NIHCCLI&II library were screened with a high-throughput drug discovery platform (HTP) developed previously with angiogenesis-specific protocols utilizing zebrafish. The screen resulted in 14 hit compounds that were subsequently narrowed down to one, with PD 81,723 chosen as the lead compound. PD 81,723 was validated as an inhibitor of angiogenesis in vivo in zebrafish and in vitro in human umbilical vein endothelial cells (HUVECs). Zebrafish exposed to PD 81,723 exhibited several signs of a diminished endothelial network due to the inhibition of angiogenesis. Immunochemical analysis did not reveal any significant apoptotic or mitotic activity in the zebrafish. Assays with cultured HUVECs elucidated the ability of PD 81,723 to inhibit capillary tube formation, migration, and proliferation of endothelial cells. In addition, PD 81,723 did not induce apoptosis while significantly down regulating p21, AKT, VEGFR-2, p-VEGFR-2, eNOS, and p-eNOS, with no notable change in endogenous VEGF-A in cultured HUVECs.
Topics: Angiogenesis Inhibitors; Animals; Cell Movement; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Zebrafish
PubMed: 36008455
DOI: 10.1038/s41598-022-18230-8 -
Journal For Immunotherapy of Cancer Nov 2019Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages... (Review)
Review
Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Clinical Trials as Topic; Combined Modality Therapy; Disease Susceptibility; Humans; Immunomodulation; Liver Neoplasms; Molecular Targeted Therapy; Neovascularization, Pathologic; Treatment Outcome; Tumor Microenvironment
PubMed: 31783782
DOI: 10.1186/s40425-019-0824-5 -
Cell Communication and Signaling : CCS Apr 2022Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the... (Review)
Review
Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.
Topics: Angiogenesis Inhibitors; Humans; Immunotherapy; Neoplasms; Neovascularization, Pathologic
PubMed: 35392964
DOI: 10.1186/s12964-022-00838-y -
Molecular Cancer Mar 2019Immune checkpoint inhibitor (ICI) activates host's anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI... (Review)
Review
Immune checkpoint inhibitor (ICI) activates host's anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. In clinical practice, a main concerning for choosing ICI is the low response rate. Even though multiple predictive biomarkers such as PD-L1 expression, mismatch-repair deficiency, and status of tumor infiltrating lymphocytes have been adopted for patient selection, frequent resistance to ICI monotherapy has not been completely resolved. However, some recent studies indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment. Actually, anti-angiogenesis therapy not only prunes blood vessel which is essential to cancer growth and metastasis, but also reprograms the tumor immune microenvironment. Preclinical studies demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. In mice model, combination therapy could effectively increase the ratio of anti-tumor/pro-tumor immune cell and decrease the expression of multiple immune checkpoints more than PD-1. Based on exciting results from preclinical studies, many clinical trials were deployed to investigate the synergistic effect of the combination therapy and acquired promising outcome. This review summarized the latest understanding of ICI combined anti-angiogenesis therapy and highlighted the advances of relevant clinical trials.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Immunological; B7-H1 Antigen; Drug Synergism; Humans; Immunotherapy; Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 30925919
DOI: 10.1186/s12943-019-0974-6