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Clinical and Experimental Medicine Jul 2023Curative surgery and locoregional therapy are radical therapies for patients with HCC. But more than 80% of HCC patients cannot be fitful for radical therapies because... (Review)
Review
Curative surgery and locoregional therapy are radical therapies for patients with HCC. But more than 80% of HCC patients cannot be fitful for radical therapies because of local progression or distant metastasis at initial diagnosis. Among patients with unresectable locally advanced hepatocellular carcinoma (HCC), some patients can be converted to be technically resectable by conversion treatment and salvage surgery. For unresectable locally advanced hepatocellular, conversion treatment prior to salvage surgery with transcatheter arterial chemoembolization (TACE) and other locoregional therapies improve outcomes. PD-1/PD-L1 inhibitors as immune checkpoint inhibitor (ICI) therapy which show high antineoplastic activity in HCC patients by preclinical and clinical researches can also be a good choice for conversion therapy. PD-1/PD-L1 inhibitor combined with locoregional therapy plus antiangiogenic agents or not is most potential conversion therapy comparing to PD-1 inhibitor monotherapy and PD-1/PD-L1 inhibitor combined with antiangiogenic agents or CTLA-4 inhibitor. As more clinical evidence reported, PD-1/PD-L1 immunotherapy would be widely used in conversion treatment of locally advanced hepatocellular carcinoma.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Immune Checkpoint Inhibitors; Angiogenesis Inhibitors; B7-H1 Antigen; Chemoembolization, Therapeutic; Immunotherapy
PubMed: 36018466
DOI: 10.1007/s10238-022-00873-6 -
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 -
International Journal of Nanomedicine 2019Angiogenesis, the formation of new blood vessels, is an essential component of glioblastoma (GB) progression. The development of angiogenesis inhibitor therapy,... (Review)
Review
Angiogenesis, the formation of new blood vessels, is an essential component of glioblastoma (GB) progression. The development of angiogenesis inhibitor therapy, including treatments targeting vascular endothelial growth factor (VEGF) in particular, raised new hopes for the treatment of GB, but no Phase III clinical trial to date has reported survival benefits relative to standard treatment. There are several possible reasons for this limited efficacy, including VEGF-independent angiogenesis, induction of tumor invasion, and inefficient antiangiogenic factor delivery to the tumor. Efforts have been made to overcome these limitations by identifying new angiogenesis inhibitors that target angiogenesis through different mechanisms of action without inducing tumor invasion, and through the development of viral and nonviral delivery methods to improve antiangiogenic activity. Herein, we describe the nonviral methods, including convection-enhanced delivery devices, implantable polymer devices, nanocarriers, and cellular vehicles, to deliver antiangiogenic factors. We focus on those evaluated in intracranial (orthotopic) animal models of GB, the most relevant models of this disease, as they reproduce the clinical scenario of tumor progression and therapy response encountered in GB patients.
Topics: Angiogenesis Inhibitors; Animals; Drug Carriers; Drug Delivery Systems; Glioblastoma; Humans; Nanoparticles; Neovascularization, Pathologic
PubMed: 31040671
DOI: 10.2147/IJN.S194858 -
Drug Discovery Today Nov 2017In elderly aged related macular degeneration (AMD) is the common eye disease which impairs the vision and most of the time it creates permanent vision loss. Because... (Review)
Review
In elderly aged related macular degeneration (AMD) is the common eye disease which impairs the vision and most of the time it creates permanent vision loss. Because elderly population constitute the larger percentage among society, visual loss due to AMD has become a growing problem. Despite the advances made in developing therapeutics, there is still no satisfactory treatment. The limitations of the available treatments are due to the absence of potent, non-invasive therapy. Furthermore, part of the available drugs targets angiogenesis and create a hypoxic environment that augment further angiogenesis. Therefore, it is reasonable to consider eye integrity and the correlation between hypoxia and angiogenesis before developing successful drugs. This review highlighted issues regarding the available therapeutic strategies and explored whether AMD can be managed by employing specific nanoformulations.
Topics: Aged; Angiogenesis Inhibitors; Animals; Drug Delivery Systems; Drug Design; Humans; Macular Degeneration; Nanoparticles
PubMed: 28782687
DOI: 10.1016/j.drudis.2017.07.010 -
Drug Discovery Today Feb 2015Angiogenesis is an exquisitely regulated process that is required for physiological processes and is also important in numerous diseases. Tumors utilize angiogenesis to... (Review)
Review
Angiogenesis is an exquisitely regulated process that is required for physiological processes and is also important in numerous diseases. Tumors utilize angiogenesis to generate the vascular network needed to supply the cancer cells with nutrients and oxygen, and many cancer drugs aim to inhibit tumor angiogenesis. Anti-angiogenic therapy involves inhibiting multiple cell types, molecular targets, and intracellular signaling pathways. Computational tools are useful in guiding treatment strategies, predicting the response to treatment, and identifying new targets of interest. Here, we describe progress that has been made in applying mathematical modeling and bioinformatics approaches to study anti-angiogenic therapeutics in cancer.
Topics: Angiogenesis Inhibitors; Drug Discovery; Humans; Models, Biological; Neoplasms; Systems Biology
PubMed: 25286370
DOI: 10.1016/j.drudis.2014.09.026 -
Drug Design, Development and Therapy 2015As tumor angiogenesis is one of the hallmarks of cancer, the inhibition of vascular endothelial growth factor signaling has become an attractive anticancer approach.... (Review)
Review
As tumor angiogenesis is one of the hallmarks of cancer, the inhibition of vascular endothelial growth factor signaling has become an attractive anticancer approach. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, has demonstrated encouraging anticancer activity across a broad range of malignancies, including gastric cancer, non-small-cell lung cancer, breast cancer, and hepatocellular carcinoma. In this up-to-date review, focus is not only on the structure, mechanisms, and pharmacokinetics of apatinib, but also on summarizing clinical trials and making recommendations of apatinib for patients with advanced solid tumors.
Topics: Angiogenesis Inhibitors; Animals; Humans; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Pyridines; Signal Transduction; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2
PubMed: 26622168
DOI: 10.2147/DDDT.S97235 -
Medical Oncology (Northwood, London,... Nov 2022This study aimed to evaluate the effect of dual-frequency sonication in the presence of thalidomide angiogenesis inhibitor and nanomicelles containing doxorubicin on...
The effect of dual-frequency sonication in the presence of thalidomide angiogenesis inhibitor and nanomicelles containing doxorubicin on inhibiting the growth and angiogenesis of breast adenocarcinoma in vivo.
This study aimed to evaluate the effect of dual-frequency sonication in the presence of thalidomide angiogenesis inhibitor and nanomicelles containing doxorubicin on inhibiting the growth and angiogenesis of breast adenocarcinoma in BALB/c female mice. Sixty mice carrying the tumor were divided into 12 groups: (A) control, (B) 28 kHz and 3 MHz sonication, (C) thalidomide, (D) thalidomide and 28 kHz, (E) thalidomide and 3 MHz, (F) thalidomide and dual-frequency sonication, (G) doxorubicin, (H) nanomicelles containing doxorubicin, (I) nanomicelles containing doxorubicin and dual-frequency sonication, (J) thalidomide and doxorubicin, (K) thalidomide and nanomicelles containing doxorubicin, and (L) thalidomide and nanomicelles containing doxorubicin and dual-frequency sonication. The delay in the tumor growth and angiogenesis percent were extracted. Pathological and immunohistochemical studies were performed to confirm the treatment. The findings of tumor growth retardation parameters and animal survival were significantly different in group L from all groups (P < 0.05). The highest rate of inhibition was in group L with a 46% inhibition. In group L, 100% of the animals survived until day 49. In groups F, C, G, B, and A, all the animals survived 45, 42, 39, 32, and 30 days, respectively. Pathological results showed a decrease in tumor grade in groups K and L. Histopathological results demonstrate a decrease in group L angiogenesis compared to group C. These findings were consistent with the results of color Doppler ultrasound imaging. Dual-frequency sonication in the presence of thalidomide and doxorubicin-containing nanomicelles inhibits tumor growth and angiogenesis.
Topics: Female; Animals; Mice; Thalidomide; Angiogenesis Inhibitors; Sonication; Doxorubicin; Neovascularization, Pathologic; Mice, Inbred BALB C; Adenocarcinoma
PubMed: 36434467
DOI: 10.1007/s12032-022-01898-3 -
Bioscience Reports Oct 2017Homocysteine (Hcy) is an intermediate non-diet amino acid connecting methionine and folate cycles. Elevated total Hcy level in blood, denoted as hyperhomocysteinemia,...
Homocysteine (Hcy) is an intermediate non-diet amino acid connecting methionine and folate cycles. Elevated total Hcy level in blood, denoted as hyperhomocysteinemia, has emerged as a prevalent and strong risk factor for multiple diseases including atherosclerotic vascular disease in coronary, cerebral, and peripheral vessels. Its detrimental effect on vascular system implies the potential application as an inhibitor of angiogenesis. However, the detailed mechanism is unveiled. Inhibitory effect of Hcy was assessed on vascular endothelial growth factor (VEGF) induced cell proliferation and migration with endothelial cell (EC) culture system. Its effect on angiogenesis was further examined and After Hcy treatment, key angiogenic factors were measured by RT-qPCR. Cellular skeletal structure was also evaluated by actin stress fiber staining. VEGF-induced human umbilical vein EC (HUVEC) proliferation and migration were dramatically down-regulated by Hcy in a dose-responsive manner. Hcy treatment significantly inhibited the VEGF-induced angiogenesis by tube formation assay and chick chorioallantoic membrane (CAM) vessel formation Key angiogenic factors like VEGFR1/2 and angiopoietin (Ang)1/2 were substantially reduced by Hcy in HUVEC- and VEGF-induced actin stress fiber cytoskeletal structure was abolished. We demonstrated that Hcy could inhibit angiogenesis by targetting key angiogenic factor and disruption of actin cytoskeleton which is crucial for cell migration.
Topics: Angiogenesis Inhibitors; Animals; Cell Movement; Chickens; Chorioallantoic Membrane; Cytoskeleton; Endothelial Cells; Homocysteine; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A
PubMed: 28864781
DOI: 10.1042/BSR20170860 -
Cancer Research Oct 2022The successful development of multikinase inhibitors over the last two decades has revolutionized the management of many malignant cancers. Agents such as the...
The successful development of multikinase inhibitors over the last two decades has revolutionized the management of many malignant cancers. Agents such as the antiangiogenic kinase inhibitor sorafenib have certain advantages such as a broad spectrum of activity against cancer cells, vascular endothelial cells, and pericytes, and are the mainstay of treatment in diseases such as advanced renal or liver cancer. The more recent emergence of immunotherapy-using immune checkpoint blockade-in some of the same diseases has raised important questions about the treatment interaction with antiangiogenic drugs, seven such combinations have been approved for lung, liver, kidney, and endometrial cancers, and multiple combination therapies are being aggressively pursued in the clinic. Thus, revealing mechanisms of action of antiangiogenic kinase inhibitors in combination with immune checkpoint blockade is critical to improving the treatment outcome further. This Landmark commentary on sorafenib in cancer therapy highlights these important questions. See related article by Wilhelm et al., Cancer Res 2004;64:7099-109.
Topics: Angiogenesis Inhibitors; Endothelial Cells; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Liver Neoplasms; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Neovascularization, Pathologic; Receptor Protein-Tyrosine Kinases; Sorafenib; Tyrosine
PubMed: 36245248
DOI: 10.1158/0008-5472.CAN-22-2639 -
Oncology Reports Feb 2022Vasculogenic mimicry (VM) is the formation of a blood supply system that confers aggressive and metastatic properties to tumors and correlates with a poor prognosis in...
Vasculogenic mimicry (VM) is the formation of a blood supply system that confers aggressive and metastatic properties to tumors and correlates with a poor prognosis in cancer patients. Thus, the inhibition of VM is considered an effective approach for cancer treatment, although such a mechanism remains poorly described. In the present study, we examined methionine aminopeptidase‑2 (MetAP2), a key factor of angiogenesis, and demonstrated that it is pivotal for VM, using pharmacological and genetic approaches. Fumagillin and TNP‑470, angiogenesis inhibitors that target MetAP2, significantly suppressed VM in various human cancer cell lines. We established MetAP2‑knockout (KO) human fibrosarcoma HT1080 cells using the CRISPR/Cas9 system and found that VM was attenuated in these cells. Furthermore, re‑expression of wild‑type MetAP2 restored VM in the MetAP2‑KO HT1080 cells, but the substitution of D251, a conserved amino acid in MetAP2, failed to rescue the VM. Collectively, our results demonstrate that MetAP2 is critical for VM in human cancer cells and suggest fumagillin and TNP‑470 as potent VM‑suppressing agents.
Topics: Aminopeptidases; Angiogenesis Inhibitors; CRISPR-Cas Systems; Cell Line, Tumor; Cyclohexanes; Fatty Acids, Unsaturated; Fibrosarcoma; Gene Knockdown Techniques; Humans; Metalloendopeptidases; Methionyl Aminopeptidases; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes
PubMed: 34913067
DOI: 10.3892/or.2021.8242