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Angiogenesis Aug 2023In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different... (Review)
Review
In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.
Topics: Female; Humans; COVID-19; SARS-CoV-2; Neovascularization, Pathologic; Neoplasms; Endothelial Cells; Angiogenesis Inhibitors
PubMed: 37060495
DOI: 10.1007/s10456-023-09876-7 -
Current Treatment Options in Oncology Dec 2023The treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to... (Review)
Review
The treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to extirpative therapy in appropriately selected patients. Stereotactic body radiation therapy (SBRT) is an emerging noninvasive alternative to treat primary RCC tumors. The advent of immune checkpoint inhibitors (ICIs) has greatly improved the overall survival of advanced RCC, and now the ICI-based doublet (dual ICI-ICI doublet; or ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor, ICI-TKI doublet) has become the standard frontline therapy. Based on unprecedented outcomes in the metastatic with ICIs, they are also being explored in the neoadjuvant and adjuvant setting for patients with high-risk disease. Adjuvant pembrolizumab has proven efficacy to reduce the risk of RCC recurrence after nephrectomy. Historically considered a radioresistant tumor, SBRT occupies an expanding role to treat RCC with oligometastasis or oligoprogression in combination with systemic therapy. Furthermore, SBRT is being investigated in combination with ICI-doublet in the advanced disease setting. Lastly, given the treatment paradigm is shifting to adopt ICIs at earlier disease course, the prospective studies guiding treatment sequencing in the post-ICI setting is maturing. The effort is ongoing in search of predictive biomarkers to guide optimal treatment option in RCC.
Topics: Humans; Carcinoma, Renal Cell; Prospective Studies; Vascular Endothelial Growth Factor A; Neoplasm Recurrence, Local; Adjuvants, Immunologic; Angiogenesis Inhibitors; Kidney Neoplasms
PubMed: 38153686
DOI: 10.1007/s11864-023-01161-5 -
International Journal of Molecular... Dec 2023Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives,... (Review)
Review
Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives, there is currently no fully effective treatment for this disease. In the current era, multiple drugs are being developed for the treatment of autoimmune diseases. This review assesses the available evidence on the pathogenesis of vitiligo, and a comprehensive review of treatments available for vitiligo now and in the near future is provided. This qualitative analysis spans 116 articles. We reviewed the mechanism of action, efficacy and safety data of phototherapy, afamelanotide, cyclosporine, phosphodiesterase 4 inhibitors, trichloroacetic acid, basic fibroblast growth factor, tumor necrosis factor (TNF) inhibitors, secukinumab, pseudocatalase and janus kinase (JAK) inhibitors. At the moment, there is no clearly outstanding option or fully satisfactory treatment for vitiligo, so it is necessary to keep up the development of new drugs as well as the publication of long-term effectiveness and safety data for existing treatments.
Topics: Humans; Vitiligo; Quality of Life; Janus Kinase Inhibitors; Phototherapy; Treatment Outcome
PubMed: 38139134
DOI: 10.3390/ijms242417306 -
Cancer Immunology, Immunotherapy : CII Dec 2023Colorectal cancer (CRC) is the second most common cause of cancer mortality, with mismatch repair proficient (pMMR) and/or microsatellite stable (MSS) CRC making up more... (Review)
Review
Colorectal cancer (CRC) is the second most common cause of cancer mortality, with mismatch repair proficient (pMMR) and/or microsatellite stable (MSS) CRC making up more than 80% of metastatic CRC. Programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) immune checkpoint inhibitors (ICIs) are approved as monotherapy in many cancers including a subset of advanced or metastatic colorectal cancer (CRC) with deficiency in mismatch repair (dMMR) and/or high microsatellite instability (MSI-H). However, proficient mismatch repair and microsatellite stable (pMMR/MSS) cold CRCs have not shown clinical response to ICIs alone. To potentiate the anti-tumor response of PD-L1/PD-1 inhibitors in patients with MSS cold cancer, combination strategies currently being investigated include dual ICI, and PD-L1/PD-1 inhibitors in combination with chemotherapy, radiotherapy, vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors, mitogen-activated protein kinase (MEK) inhibitors, and signal transducer and activation of transcription 3 (STAT3) inhibitors. This paper will review the mechanisms of PD-1/PD-L1 ICI resistance in pMMR/MSS CRC and potential combination strategies to overcome this resistance, summarize the published clinical experience with different combination therapies, and make recommendations for future avenues of research.
Topics: Humans; B7-H1 Antigen; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Vascular Endothelial Growth Factor A; Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Microsatellite Instability
PubMed: 37831146
DOI: 10.1007/s00262-023-03520-5 -
European Journal of Pharmacology Jun 2023Angiogenesis is a double-edged sword; it is a mechanism that defines the boundary between health and disease. In spite of its central role in physiological homeostasis,... (Review)
Review
Angiogenesis is a double-edged sword; it is a mechanism that defines the boundary between health and disease. In spite of its central role in physiological homeostasis, it provides the oxygen and nutrition needed by tumor cells to proceed from dormancy if pro-angiogenic factors tip the balance in favor of tumor angiogenesis. Among pro-angiogenic factors, vascular endothelial growth factor (VEGF) is a prominent target in therapeutic methods due to its strategic involvement in the formation of anomalous tumor vasculature. In addition, VEGF exhibits immune-regulatory properties which suppress immune cell antitumor activity. VEGF signaling through its receptors is an integral part of tumoral angiogenic approaches. A wide variety of medicines have been designed to target the ligands and receptors of this pro-angiogenic superfamily. Herein, we summarize the direct and indirect molecular mechanisms of VEGF to demonstrate its versatile role in the context of cancer angiogenesis and current transformative VEGF-targeted strategies interfering with tumor growth.
Topics: Humans; Angiogenesis Inhibitors; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 36906141
DOI: 10.1016/j.ejphar.2023.175586 -
Drug Design, Development and Therapy 2023Degenerative eye conditions such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion are major contributors to significant vision... (Review)
Review
Degenerative eye conditions such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion are major contributors to significant vision loss in developed nations. The primary therapeutic approach for managing complications linked to these diseases involves the intravitreal delivery of anti-vascular endothelial growth factor (VEGF) treatments. Faricimab is a novel, humanised, bispecific antibody that simultaneously binds all VEGF-A isoforms and Angiopoietin-2, which has been approved by regulatory agencies, such as the US Food and Drug Administration (FDA), the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA), for the treatment of neovascular AMD and diabetic macular oedema (DMO). Intravitreal faricimab holds the promise of reducing the treatment burden for patients with these conditions by achieving comparable or superior therapeutic outcomes with fewer clinic visits. The scope of faricimab's application includes addressing complex macular conditions such as DMO. This review intends to elucidate the distinctive pharmacological characteristics of faricimab and provide an overview of the key clinical trials and real-world studies that assess its effectiveness and safety in treating degenerative macular diseases.
Topics: Humans; Vascular Endothelial Growth Factor A; Ranibizumab; Angiogenesis Inhibitors; Bevacizumab; Receptors, Vascular Endothelial Growth Factor; Visual Acuity; Wet Macular Degeneration; Macular Edema; Diabetic Retinopathy; Intravitreal Injections
PubMed: 37746113
DOI: 10.2147/DDDT.S427416 -
Investigative Ophthalmology & Visual... Oct 2023Microaneurysm (MA) plays an important role in the pathogenesis of diabetic macular edema (DME) progression and response to anti-vascular endothelial growth factor (VEGF)...
PURPOSE
Microaneurysm (MA) plays an important role in the pathogenesis of diabetic macular edema (DME) progression and response to anti-vascular endothelial growth factor (VEGF) therapy. This study aimed to investigate the effect of faricimab, a bispecific antibody against angiopoietin-2 and VEGF, on the number of MAs and their turnover in the treatment of DME.
METHODS
We included that patients with DME who underwent three monthly injections of faricimab in one eye, with the other eye as control. We examined central retinal thickness (CRT) based on optical coherence tomography (OCT) and best-corrected visual acuity. Turnover, including loss and newly formed MAs, and the total number of MAs were counted based on merged images of the OCT map and fluorescein angiography.
RESULTS
We enrolled 28 patients with DME. After 3 monthly injections of faricimab, CRT significantly improved, 66.0 ± 16.2% of MAs disappeared, and 6.71 ± 5.6% of new MAs were generated, resulting in total reduction to 40.7 ± 15.2%. In the treated eyes, MA disappearance (P < 0.0001) and turnover (P = 0.007) were significantly greater, and new formation was smaller (P < 0.0001) than in non-treated eyes. The size of the retained MAs decreased after treatment. Microaneurysm turnover was not significantly different between areas with and without edema before treatment.
CONCLUSIONS
In the process of improving edema in DME with faricimab, MAs shrink and disappear, and formation of MAs are inhibited, resulting in decreased total number of MAs. Intravitreal administration of faricimab suppresses vascular permeability and improves vascular structure.
Topics: Humans; Macular Edema; Diabetic Retinopathy; Vascular Endothelial Growth Factor A; Angiogenesis Inhibitors; Microaneurysm; Intravitreal Injections; Edema; Tomography, Optical Coherence; Diabetes Mellitus
PubMed: 37856112
DOI: 10.1167/iovs.64.13.31 -
Eye (London, England) Dec 2023Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD).
BACKGROUND/OBJECTIVE
Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD).
SUBJECTS/METHODS
Multicenter, retrospective chart review was conducted on patients treated with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid.
RESULTS
After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a - 31.3 μM (p < 0.001), a - 25.3 μM (p < 0.001) and a - 84.5 μM (p < 0.001) reduction in CST, respectively. After three injections of faricimab, all eyes (n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a - 43.4 μM (p < 0.001), a - 38.1 μM (p < 0.001) and a - 80.1 μM (p < 0.204) reduction in CST, respectively. One case of intraocular inflammation was observed after four injections of faricimab and resolved with topical steroids. One case of infectious endophthalmitis was treated with intravitreal antibiotics and resolved.
CONCLUSIONS
Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD.
Topics: Humans; Angiogenesis Inhibitors; Retrospective Studies; Treatment Outcome; Intravitreal Injections; Macular Degeneration; Inflammation
PubMed: 37173428
DOI: 10.1038/s41433-023-02553-5 -
Ophthalmology Jun 2024To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME).
DESIGN
Randomized, double-masked, noninferiority phase 3 trials.
PARTICIPANTS
Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME.
METHODS
Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change.
MAIN OUTCOME MEASURES
Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100.
RESULTS
In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept.
CONCLUSIONS
Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Macular Edema; Diabetic Retinopathy; Visual Acuity; Intravitreal Injections; Double-Blind Method; Male; Female; Middle Aged; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Aged; Tomography, Optical Coherence; Treatment Outcome; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Angiopoietin-2; Follow-Up Studies; Antibodies, Monoclonal, Humanized
PubMed: 38158159
DOI: 10.1016/j.ophtha.2023.12.026