Anti-angiogenesis clinical trials -
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Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K, Tisdale M. Characterization of a cancer cachectic factor. Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Flechon A, Skoneczna I, et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer VENICE : a phase 3, double-blind randomised trial.
Lancet Oncol. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy REVEL : a multicentre, double-blind, randomised phase 3 trial.
Positive and negative modulation of angiogenesis by VEGFR1 ligands. Sci Signal. Cao Y, Zhong W, Sun Y. Improvement of antiangiogenic cancer therapy by understanding the mechanisms of angiogenic factor interplay and drug resistance.
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Maynard MA, Marino-Enriquez A, Fletcher JA, Dorfman DM, Raut CP, Yassa L, et al. Thyroid hormone inactivation in gastrointestinal stromal tumors. Jubb AM, Pham TQ, Hanby AM, Frantz GD, Peale FV, Wu TD, et al. Expression of vascular endothelial growth factor, hypoxia inducible factor 1alpha, and carbonic anhydrase ix in human tumours.
J Clin Pathol. Xue Y, Religa P, Cao R, Hansen AJ, Lucchini F, Jones B, et al. Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome.
Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE.
Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell.
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Cancer Med. Nissen LJ, Cao R, Hedlund EM, Wang Z, Zhao X, Wetterskog D, et al. Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, et al.
Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.
Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.
Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.
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Molecular markers to predict response to therapy. Semin Oncol. Maru D, Venook AP, Ellis LM. Predictive biomarkers for bevacizumab: are we there yet? Clin Cancer Res. Pohl M, Werner N, Munding J, Tannapfel A, Graeven U, Nickenig G, et al.
Biomarkers of anti-angiogenic therapy in metastatic colorectal cancer mCRC : original data and review of the literature. Z Gastroenterol. Niers TM, Richel DJ, Meijers JC, Schlingemann RO. Vascular endothelial growth factor in the circulation in cancer patients may not be a relevant biomarker.
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Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Bunni J, Shelley-Fraser G, Stevenson K, Oltean S, Salmon A, Harper SJ, et al. Circulating levels of anti-angiogenic VEGF-A isoform VEGF-AXXXB in colorectal cancer patients predicts tumour VEGF-A ratios.
Am J Cancer Res. PubMed Central PubMed Google Scholar. Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. Chen C, Sun P, Ye S, Weng HW, Dai QS. Hypertension as a predictive biomarker for efficacy of bevacizumab treatment in metastatic colorectal cancer: a meta-analysis.
J BUON. PubMed Google Scholar. Penzvalto Z, Surowiak P, Gyorffy B. Biomarkers for systemic therapy in ovarian cancer. Angiogenesis inhibitors for cancer can be prescribed by a doctor to take orally by mouth or intravenously by vein; IV.
If you are prescribed an oral angiogenesis inhibitor to take at home, ask if you need to fill the prescription at a pharmacy that handles complex medications, such as a specialty pharmacy. Check with the pharmacy and your insurance company about your insurance coverage and co-pay of the oral medication.
Also, be sure to ask about how to safely store and handle your prescription at home. If you are prescribed an IV treatment, that will be given at the hospital or other cancer treatment facility. Talk with your treatment center and insurance company about how your specific prescription is covered and how any co-pays will be billed.
If you need financial assistance, talk with your health care team, including the pharmacist or a social worker , about co-pay assistance options. National Cancer Institute: Angiogenesis Inhibitors. The Angiogenesis Foundation: Treatments.
Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology ASCO , the voice of the world's oncology professionals.
org Conquer Cancer ASCO Journals Donate. What is Targeted Therapy? Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Understanding Pharmacogenomics Radiation Therapy Surgery When to Call the Doctor During Cancer Treatment What is Maintenance Therapy?
Veterans Prevention and Healthy Living Cancer. Net Videos Coping With Cancer Research and Advocacy Survivorship Blog About Us. Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Approved by the Cancer. What is angiogenesis? H ow do angiogenesis inhibitors treat cancer?
What angiogenesis inhibitors are approved to treat cancer? Thalidomide is not recommended during pregnancy because it causes severe birth defects.
Vandetanib Caprelsa is approved to treat: Medullary thyroid cancer Ziv-aflibercept Zaltrap is approved to treat: Colorectal cancer Researchers are studying whether some of these drugs may treat other types of cancer. Therefore, it is important to summarise the results of these recent studies and to compare the drugs to each other.
This knowledge will help anticancer research move forward, as emerging therapies and promising clinical agents are highlighted in this review to point out future directions of this field. Ogasawara et al. The results show that lenvatinib induced dose- and time-dependent growth suppression of HCC cell lines, with no signs of apoptosis.
Cell lines expressing FGFR1, -2, -3 and -4, FGF19, FRS2α fibroblast growth factor receptor substrate 2 alpha and RET showed the greatest response to treatment. In the in vivo study, lenvatinib-treated mice showed dose-dependent inhibition of tumour growth. In addition, a decrease in blood vessel density and an increase in necrosis were observed in mice, but again no signs of apoptosis were observed.
Therefore, this study demonstrates the antiproliferative and anti-angiogenic effects of lenvatinib on liver cancer cells both in vitro and in vivo , indicating that it could be a promising treatment for patients with HCC.
Indeed, lenvatinib is currently used in patients with advanced HCC, and, although the clinical benefits remain limited [ ] , lenvatinib also seems to delay functional deterioration in these patients, helping with the preservation of health-related quality of life during treatment [ ].
In another more recent study on lenvatinib, Jin et al. This drug combination resulted in synthetic lethality against HCC both in vitro and in vivo in patient-derived HCC tumours in mice. The mechanistic studies showed that gefitinib was able to abrogate the feedback activation of the EGFR-PAK2 [P21 RAC1 activated kinase 2]-ERK5 extracellular signal-regulated kinase 5 signalling pathway that was induced by the inhibition of FGFR by lenvatinib.
The combination treatment was subsequently administered to 12 patients unresponsive to lenvatinib with advanced HCC, where a better clinical response was achieved, proposing this regimen as a novel strategy for advanced HCC patients with overexpression of EGFR.
Anlotinib is a multiple kinase inhibitor that has shown efficacy against various types of cancer [ , ]. To date, no effective treatment has been found for patients with poorly differentiated papillary thyroid cancer PTC or anaplastic thyroid cancer ATC [ ] , a recent study aimed to investigate the effect of anlotinib against thyroid cancer in vitro and in vivo [ ].
The results show growth inhibition of ATC and PTC cells in vitro with IC 50 values of 3. In addition, anlotinib inhibited cell migration, as well as the in vivo growth of thyroid tumours transplanted to mice. Thus, this study shows that anlotinib has anticancer activity and could be considered as an effective therapeutic approach for patients with advanced thyroid carcinoma.
For more effective delivery of anlotinib, Gao et al. The hydrogel was prepared by encapsulating anlotinib with hyaluronic acid-tyramine HA-Tyr conjugates AL-HA-Tyr.
The in vitro investigation showed that AL-HA-Tyr successfully suppressed the angiogenic capacity and proliferation of HUVECs and LLC cells, respectively.
In addition, inhibition of invasion and migration of HUVECs and LLC cells was observed. In the in vivo studies, LLC mouse models were treated with oral saline solution, oral anlotinib or intratumoral injection of HA-Tyr or AL-HA-Tyr. AL-HA-Tyr reduced visceral toxicity and downregulated Ki67 and VEGF-A in cancer cells, increasing mouse survival.
Thus, this study proposes a more effective anlotinib delivery strategy in order to reduce the systemic toxicity of anlotinib and potentiate its efficacy. Goff et al. At the same time, this molecule is involved in pathways that contribute to tumour growth, angiogenesis and metastasis [ , ].
One of the double inhibitors developed, R, showed comparable activity to sunitinib against breast cancer and renal cell carcinoma xenograft models.
Thus, it appears that dual inhibition of Axl receptor and VEGFR may be an effective anticancer treatment comparable to the known anti-angiogenic agent sunitinib. Previously reported data show that FGF promotes angiogenic signalling in HCC through the activation of the VEGF pathway [ - ].
Therefore, infigratinib-a pan-FGFR kinase inhibitor-was explored for its potential to overcome HCC resistance to VEGF-targeting drugs, such as bevacizumab [ ]. The combination regimen inhibited tumour growth, as well as invasion and metastasis to the lungs in vivo. Mice bearing high-FGFR HCC tumours showed an additional prolongation in overall survival OS.
Indeed, this combination was found effective in providing long-lasting tumour growth inhibition, reduced cell differentiation and reduced drug resistance [ ].
In a recent study, Lu et al. Indeed, the results show that anti-VEGFRAF binds effectively to VEGFR2 Ig immunoglobulin -like domain 3, thus inhibiting its interaction with VEGF-A. This led to in vitro inhibition of angiogenesis and Ab-dependent cell cytotoxicity and complement activation.
By testing the Ab activity in a mouse prostate cancer model, the treated mice showed reduced tumour growth and angiogenesis comparable with the FDA Food and Drug Administration -approved ramucirumab. In addition, the combination therapy of anti-VEGFRAF with docetaxel was even more effective in vivo against prostate cancer.
Anti-VEGFRAF treatment was also applied to mice with HL leukaemia. These mice showed increased survival and inhibition of leukemic cell metastasis to the ovaries and lymph nodes compared to ramucirumab.
Therefore, this study shows that the novel Ab anti-VEGFRAF is a potentially effective treatment for prostate cancer, leukaemia and possibly other types of cancer that overexpress VEGFR2. A novel VEGFR2 inhibitor, YLL, was recently developed against triple-negative breast cancer TNBC [ ].
Other in vitro results report inhibition of cancer cell proliferation, migration and invasion. The effects of YLL were higher than or equal to those of sorafenib, a known inhibitor of angiogenic factors such as VEGFR1, VEGFR2, VEGFR3, PDGFR-β, KIT and RET [ ].
The results of this study suggest that the VEGFR2 inhibitor YLL is a potentially useful anticancer drug. The observed resistance against clinically used anti-VEGF therapies limits the efficacy of such therapies.
This resistance could be attributed to an independent pathway of angiogenesis that can compensate for the inhibition of the VEGF-related cascade, which is mediated by 2- ω-carboxyethyl pyrrole CEP in a TLR2 Toll-like receptor 2 -dependent manner [ ]. An antibody against CEP was, thus, constructed and tested for its anti-angiogenic properties both as a monotherapy and in combination with bevacizumab [ ].
Comparing the efficacy of the combination therapy with bevacizumab monotherapy at 2. Thus, multiple targeting of angiogenic pathways may increase the efficacy of anticancer therapies. Another recent study [ ] tested the anticancer efficacy of a combination of four active ingredients [astragaloside IV, α-solanine, neferine and 2,3,5,6-tetramethylpyrazine SANT ] isolated from traditional Chinese plants against TNBC.
Overexpression of heparanase HPSE is often found in breast cancer tissues with the potential to enhance carcinogenesis and affect the process of autophagy in cancer cells [ - ]. HPSE upregulation was associated with poor outcomes in these patients.
Administration of the SANT combination resulted in in vitro inhibition of cancer cell proliferation and migration and increased the rate of autophagy in TNBC cells. Several genes were affected, and the proteomics studies found that SANT downregulated HB-EGF heparin-binding EGF-like growth factor , thrombospondin-2, amphiregulin, leptin, IGFBP-9 insulin-like growth factor-binding protein 9 , EGF, coagulation factor III and MMP-9 matrix metalloproteinase 9 , while increasing the levels of serpin E1 and platelet factor 4, proteins that play an important role in angiogenesis.
Finally, a novel Hsp90 inhibitor, AT, was recently developed against breast cancer [ ]. Hsp90 has been shown to play an important role in oncogenesis, as it regulates the stabilisation and activation of many proteins that are essential for cell survival and tumour growth [ , ].
The results of the study show that AT suppressed capillary formation, as well as the migration and invasion of HUVECs more efficiently than another Hsp90 inhibitor, AAG.
Thus, these results suggest that AT may be a new drug for the treatment of breast cancer. In , a phase II clinical trial [ ] involving patients with refractory metastatic soft tissue sarcoma after receiving anthracycline-based chemotherapy, naïve from angiogenesis inhibitors and with at least one measurable lesion according to RECIST 1.
More specifically, the median progression-free survival PFS was 5. The most common grade 3 or higher side effects associated with anlotinib treatment were hypertension, increased blood triglyceride levels and pneumothorax. No deaths were reported due to anlotinib treatment. Thus, anlotinib proved effective in increasing patient survival, while no significant adverse effects were reported.
Patients progressing after second-line or further treatment and receiving anlotinib had significantly longer OS than the placebo group, 9. In addition, a significant increase was observed in the PFS 5.
Common grade 3 or higher side effects included hypertension and hyponatremia. Therefore, the results of this study show that anlotinib is a well-tolerated further treatment, which results in a significant improvement in patients with advanced NSCLC.
Surufatinib is a small molecular inhibitor of VEGFR1, VEGFR2, VEGFR3 and FGFR1 [ ]. A randomised, double-blind, placebo-controlled, phase III study was conducted to investigate the efficacy and safety of this drug in patients with extrapancreatic neuroendocrine tumours [ ].
The study included adult patients [after receiving up to two kinds of previous systemic regimens and with unresectable or metastatic, well-differentiated, extrapancreatic neuroendocrine tumours of Eastern Cooperative Oncology Group ECOG performance status of 0 or 1] who were randomised to the surufatinib group mg or the placebo group.
The median PFS in the surufatinib group was 9. The most common grade 3 or higher side effects associated with surufatinib treatment were hypertension and proteinuria. Hence, surufatinib significantly increases the PFS of patients with progressive, advanced, well-differentiated extrapancreatic neuroendocrine tumours, while having an acceptable toxicity profile.
In a similar multicentre, randomised, double-blind, placebo-controlled, phase III trial, surufatinib was evaluated for its efficacy and safety in patients with advanced pancreatic neuroendocrine tumours [ ]. The study included adult patients after receiving up to two kinds of previous systemic regimens for advanced disease and with progressive, advanced, well-differentiated pancreatic neuroendocrine tumours of ECOG performance status of 0 or 1 who were randomised to the surufatinib mg or placebo group, both administered orally once daily in successive four-week treatment cycles.
The median PFS in the surufatinib group was The most common grade 3 or higher side effects associated with surufatinib treatment were hypertension, proteinuria and hypertriglyceridemia.
Therefore, surufatinib significantly increases the PFS of patients with pancreatic neuroendocrine tumours, as similarly reported for extrapancreatic neuroendocrine tumours. The drug has significant toxicity, which, however, is acceptable when compared to its overall benefit.
Based on the above trials, surufatinib received its first approval in China for the treatment of late-stage, well-differentiated, extrapancreatic neuroendocrine tumours in December [ ]. Surufatinib is currently in preregistration in China for pancreatic neuroendocrine tumours and in the USA for pancreatic and extrapancreatic neuroendocrine tumours, while other ongoing clinical trials are investigating its benefit for other solid tumours, including thyroid cancer, biliary tract carcinoma and soft tissue sarcoma.
The highest dose of lenvatinib 24 mg daily plus pembrolizumab was associated with two grade 3 toxicities arthralgia and fatigue , so the recommended phase II dose of lenvatinib was established at 20 mg daily plus pembrolizumab.
The most common side effects reported were fatigue, diarrhoea, hypertension and hypothyroidism. Thus, the combination of lenvatinib with pembrolizumab in patients with advanced solid tumours shows good efficacy, while the side effects observed are manageable.
Previous studies have shown that the combination of PD-1 programmed cell death protein 1 checkpoint inhibitors with VEGF-pathway TKIs leads to increased cytotoxicity and decreased cancer cell growth, but it is also related to severe side effects [ ].
Based on this, Atkins et al. Thus, the combination therapy of axitinib and pembrolizumab appears to be a relatively well-tolerated treatment, with significant efficacy against treatment-naïve advanced renal cell carcinoma.
A subsequent phase III clinical trial trying to assess the long-term efficacy and safety of the combination of pembrolizumab mg intravenously, every three weeks for up to 35 cycles with axitinib 5 mg orally, twice daily , showed increased efficacy of the combination treatment over sunitinib monotherapy 50 mg orally, once daily for four weeks per six-week cycle in treatment-naive, advanced renal cell carcinoma [ ].
Of the registered patients with a median follow-up of Therefore, the combination treatment has a superior clinical benefit over sunitinib monotherapy and can be considered as the first-line treatment for advanced renal cell carcinoma patients.
Regorafenib is an oral diphenylurea multikinase inhibitor against angiogenic VEGFR1, VEGFR2, VEGFR3 and TIE2 , stromal PDGFR-β and FGFR and oncogenic receptor tyrosine kinases KIT, RET and RAF , which has been established for metastatic colorectal cancer [ , ].
The median PFS achieved was 3. The most common grade 3 or higher side effects were hypertension, hand-foot skin reaction and hypophosphataemia, with no treatment-related deaths.
Hence, this study shows that regorafenib is an effective treatment for chemotherapy-refractory metastatic colorectal cancer with an acceptable safety profile.
The overexpression of α-fetoprotein in patients with advanced HCC has been correlated with poor prognosis [ - ]. The median follow-up was 7. However, the analysis of the results did not show a significant difference in the objective response and the median deterioration time between the two groups.
Common grade 3 or higher treatment-related adverse effects were hypertension, hyponatraemia and elevated aspartate aminotransferase. Ramucirumab-related side effects were also responsible for the death of three patients.
Hence, this study shows that ramucirumab is a potentially useful treatment for patients with advanced HCC and α-fetoprotein overexpression previously on sorafenib, although the treatment causes significant side effects, and further studies are needed to gain statistically significant results.
TAS, an oral nucleoside anticancer agent that combines trifluridine and tipiracil, has shown a significant OS prolongation in patients with refractory metastatic colorectal cancer [ ]. The co-treatment of TAS with bevacizumab has also shown promising results in colorectal cancer xenograft models compared to the corresponding monotherapies [ ].
Thus, Kuboki et al. After 16 weeks of treatment, PFS was achieved in The most common grade 3 or higher side effects observed in patients were neutropenia, leukopenia, anaemia, febrile neutropenia and thrombocytopenia.
Serious adverse reactions were reported in only three patients, but no deaths were reported due to the regimen. This study shows that the combination of TAS with bevacizumab has significant efficacy in patients with refractory metastatic colorectal cancer, while it is a treatment that does not present significant overall toxicity.
The aim of the phase II study by Palazzo et al. An objective response was observed in 30 patients and a pathologic complete remission pCR in 10 of the 34 patients.
This study showed that this neoadjuvant therapy, including chemotherapy and anti-angiogenic treatment, significantly increases disease-free survival and OS for patients with inflammatory breast cancer.
Another recent phase II study evaluated the efficacy and safety of a treatment that included apatinib mg orally once daily and etoposide 50 mg orally once daily on Days of a day cycle for up to six cycles in patients with platinum-resistant or platinum-refractory ovarian cancer [ ].
Of the 35 patients in the study, 19 showed an objective response to treatment, while the most common grade 3 or higher side effects observed were neutropenia, fatigue, anaemia and mucositis, and two patients developed severe side effects.
However, no treatment-related deaths were reported. Therefore, the combination of apatinib with etoposide seemed to be significantly effective in more than half of the platinum-resistant ovarian cancer patients registered in the present study, with manageable adverse reactions.
The aim of this review article is to present the most up-to-date data on novel anti-angiogenic factors that are under development or clinical evaluation.
In total, 15 different anti-angiogenic agents are included based on recent publications of the last five years, which confirms that the discovery of anti-angiogenic factors has been an active and ongoing field of research.
The obvious disadvantage of preclinical studies is that the pharmacokinetics and possible side effects of the proposed drugs are usually not studied. Indeed, a regimen may be effective in vitro and in vivo but toxic for humans and, therefore, not pursued further.
In addition, we must always consider the differences between the in vivo models and humans, which may be responsible for the clinical failure of preclinically identified promising agents. In this scope, both preclinical and clinical studies of lenvatinib and anlotinib are included to follow up on the overall efficacy of these two agents.
Lenvatinib showed promising in vitro and in vivo antiproliferative and anti-angiogenic activity against liver cancer cells [ ]. As proof of concept, lenvatinib showed a significant response rate in patients with metastatic renal cell carcinoma, endometrial cancer, squamous cell carcinoma of the head and neck, melanoma, non-small cell lung cancer and urothelial carcinoma, while it was not correlated with serious side effects [ ].
Anlotinib was found cytotoxic against thyroid cancer cells, suppressed in vitro migration and decreased tumour growth in vivo [ ]. In clinical trials, anlotinib was effective against refractory soft tissue sarcoma [ ] and non-small cell lung cancer [ ].
Although no treatment-related deaths were reported, several adverse reactions were observed in patients in both clinical trials. Of particular interest are the results of a recent study [ ] where, to avoid anlotinib-related systemic side effects, a hydrogel containing anlotinib was manufactured, followed by an intratumoral injection to a mouse model of Lewis lung cancer.
The results are particularly encouraging, giving new hope for providing targeted therapies with increased efficacy and reduced side effects via novel delivery systems. Several other anti-angiogenic agents under preclinical development are also discussed, including YLL for breast cancer [ ] , R for breast and renal cancer [ ] and AT for breast cancer [ ].
Recently completed clinical trials with positive results are also presented, namely for monotherapies such as oral surufatinib against pancreatic and extrapancreatic neuroendocrine cancers, even though severe side effects were reported [ , ] , and regorafenib against advanced colorectal cancer [ ].
In addition, ramucirumab, a mAb under development, was clinically tested against advanced hepatocellular carcinoma in patients with increased α-fetoprotein levels, where it showed high efficacy [ ]. Finally, the combination of chemotherapeutics with different mechanisms of action is a common practice in cancer patient care; therefore, some studies with combination regimens are also discussed here.
Indicatively, bevacizumab was combined with carboplatin, paclitaxel and metronomic cyclophosphamide, where it was found useful against inflammatory breast cancer [ ] , and in another clinical trial, it was combined with TAS against metastatic colorectal cancer, where again positive results were obtained [ ].
Moreover, apatinib combined with etoposide was effective against ovarian cancer unresponsive to platinum [ ] , whereas an anti-PD-1 mAb combined with axitinib also showed an increased patient response, although several side effects were induced [ , ]. Summaries of the presented anti-angiogenic agents categorised into preclinical and clinical studies, along with the main findings of each study, are shown in Tables 1 and 2.
Summary of the anti-angiogenic agents currently being tested in pre-clinical models discussed in this article.
Summary of the anti-angiogenic agents currently in clinical trials discussed in this article. It should be noted that most clinical studies found treatment-related side effects, which were mostly mild, while few deaths were reported. However, since most of the studies include patients with highly resistant or metastatic cancers that do not respond to other treatments, the overall efficacy of these therapies in prolonging patient survival outweighs the frequent side effects.
Cancer is a global epidemic and the second most common cause of death. Despite the active research, it remains a condition that, in most cases, is not cured and leads to death. Observing the distinctive physiology of cancer cells, the angiogenesis pathway emerged as a promising anticancer target.
Thus, in recent years, more and more researchers are aiming to develop various anti-angiogenic agents and regulate their efficacy and safety. Regarding this, the present review summarises the results of very recent preclinical and clinical studies involving monotherapies or combination therapies of anti-angiogenic agents, in order to highlight the updates in the field and encourage more related research.
Apart from these therapies, however, several other anti-angiogenic approaches are currently being explored, such as the use of natural phytochemicals as anti-angiogenic agents in cancer [ ]. However, the clinical translation of dietary phytochemicals still faces challenges, as the results thus far remain limited, contradictory, inconclusive or even inexistent for some of these compounds.
In this context, a significant effort is needed to improve clinical trial design, taking serious consideration of the target population, as well as the pharmacokinetic and pharmacodynamic properties of these compounds. Other novel anti-angiogenic strategies include the exploitation of miRNAs-elucidating their role in angiogenesis and evaluating novel miRNA-mediated immunotherapies [ ].
Advances in miRNA targeting and delivery strategies, such as the use of nanoparticles or cell-derived membrane vesicles for therapeutic miRNA delivery, may provide miRNA-based therapeutics as anti-angiogenic treatments.
Additionally, the use of anti-angiogenic peptides has emerged as a promising anticancer strategy, as they present several advantages, with rapid production through automated chemical synthesis and the ability to undergo structural modifications. Therefore, several anticancer peptides that have been discovered derive from nanobodies and mimotopes resources, as well as natural resources such as venoms, bacteria, fungi, sponges, animals and plants [ ].
The new methods available in phage display and peptidomimetics have contributed to the development of new anti-angiogenic peptides, while the novel technologies such as pegylation, polymer-supported formulation and macromolecule conjugation can now provide these peptides with better pharmacokinetic properties and contribute to more anti-angiogenic peptide-based therapeutics.
Although all of the above treatment strategies appear to be particularly promising for the future, the issue of developing angiogenic resistance should first be addressed. The combinatorial treatments mentioned have shown excellent results and will be a key concept of future therapeutic regimens.
Emerging ideas about novel delivery systems of such therapies might be the way forward. In addition, the simplification of regimens should be explored, especially when combination therapies are indicated, such as oral administration or the preparation of a combination formulation to increase patient adherence.
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Metrics details. Angiogenesis has Ant-iangiogenesis Anti-angiogenesis clinical trials the topic of major scientific interest Weight management program the field of malignant tumors. Nowadays, targeting Anti-angiogenesis clinical trials Anti-angiogdnesis achieved success Anti-angiogenesia various Anti-angiogenesis clinical trials by several mechanisms, including the use of anti-angiogenic small molecule receptor tyrosine kinase inhibitors TKIs. The development of TKIs targeting pro-angiogenic receptors, mainly vascular endothelial growth factor receptor VEGFR family, have significantly improved the outcome of certain types of cancers, like renal cell carcinoma, hepatocellular carcinoma, and colorectal carcinoma. However, the general response rate is not very satisfactory. Journal Anti-wngiogenesis the Egyptian National Cancer Anti-antiogenesis volume 33Article number: 15 Cite this article. Breakfast skipping and cultural influences Anti-angiogenesis clinical trials. Anti-angigenesis is trialss formation of new vascular networks from preexisting Anti-angiogenesis clinical trials through the migration and proliferation of differentiated endothelial cells. Available evidence suggests that while antiangiogenic therapy could inhibit tumour growth, the response to these agents is not sustained. The aim of this paper was to review the evidence for anti-angiogenic therapy in cancer therapeutics and the mechanisms and management of tumour resistance to antiangiogenic agents.Skip to Content. Angiogenesis Endurance nutrition for team sports are grials type of cancer treatment. They stop Anti-angiogenesiss Anti-angiogenesis clinical trials in the body called angiogenesis, or ttrials vessel formation.
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Food and Troals Administration has approved Anti-angiogenesix angiogenesis inhibitors. They may affect angiogenesis in frials than one way, and some of them can also affect other triials that a Anto-angiogenesis grows. Angiogenesis inhibitors can be given coinical or in combination with other types of clinicla.
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Talk trias your health care team about tirals trials for clinlcal inhibitors. Clinival of clunical body's Anti-angiogeneeis functions Anti-angiogenesis clinical trials on angiogenesis. Therefore, angiogenesis inhibitors Anti-sngiogenesis cause a wide range of physical coinical effects including:.
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Be Trjals to let your health care team Anti-angiogenesia Anti-angiogenesis clinical trials side effects you experience. If an angiogenesis inhibitor is recommended Anti-angiogenesid you, talk with triasl doctor about the specific triasl benefits and risks of that medication.
Also, ask about Anti-angiognesis side effects can be managed and what side effects to watch for. Angiogenesis inhibitors for cancer can be prescribed by a doctor to take orally by mouth or intravenously by vein; IV.
If you are prescribed an oral angiogenesis inhibitor to take at home, ask if you need to fill the prescription at a pharmacy that handles complex medications, such as a specialty pharmacy.
Check with the pharmacy and your insurance company about your insurance coverage and co-pay of the oral medication. Also, be sure to ask about how to safely store and handle your prescription at home. If you are prescribed an IV treatment, that will be given at the hospital or other cancer treatment facility.
Talk with your treatment center and insurance company about how your specific prescription is covered and how any co-pays will be billed. If you need financial assistance, talk with your health care team, including the pharmacist or a social workerabout co-pay assistance options.
National Cancer Institute: Angiogenesis Inhibitors. The Angiogenesis Foundation: Treatments. Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology ASCOthe voice of the world's oncology professionals.
org Conquer Cancer ASCO Journals Donate. What is Targeted Therapy? Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Understanding Pharmacogenomics Radiation Therapy Surgery When to Call the Doctor During Cancer Treatment What is Maintenance Therapy? Veterans Prevention and Healthy Living Cancer.
Net Videos Coping With Cancer Research and Advocacy Survivorship Blog About Us. Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Approved by the Cancer. What is angiogenesis? H ow do angiogenesis inhibitors treat cancer? What angiogenesis inhibitors are approved to treat cancer?
Thalidomide is not recommended during pregnancy because it causes severe birth defects. Vandetanib Caprelsa is approved to treat: Medullary thyroid cancer Ziv-aflibercept Zaltrap is approved to treat: Colorectal cancer Researchers are studying whether some of these drugs may treat other types of cancer.
What are the side effects of angiogenesis inhibitors? Therefore, angiogenesis inhibitors can cause a wide range of physical side effects including: High blood pressure A rash or dry, itchy skin Hand-foot syndromewhich causes tender, thickened areas on your palms and soles.
Diarrhea Fatigue Low blood counts Problems with wound healing or cuts reopening Although common, these side effects do not happen with every drug or every person.
Rare side effects include: Serious bleeding Heart attacks Heart failure Blood clots Holes in the intestines, called bowel perforations If an angiogenesis inhibitor is recommended for you, talk with your doctor about the specific potential benefits and risks of that medication.
How are angiogenesis inhibitors given? Questions to ask your health care team Consider asking these questions about angiogenesis inhibitors: Do you recommend an angiogenesis inhibitor as part of my treatment plan? Which one? What are the possible risks and benefits of the drug?
What are the potential short- and long-term side effects of this medication? How long will this treatment last? How is this drug different from chemotherapy or other treatments? Will I take this drug at home or at the hospital? Will I need other cancer treatments in addition to this angiogenesis inhibitor?
Which clinical trials are options for me? Who can help me manage the costs of my prescriptions? Related Resources Understanding Targeted Therapy Skin Reactions to Targeted Therapy and Immunotherapy More Information National Cancer Institute: Angiogenesis Inhibitors The Angiogenesis Foundation: Treatments.
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: Anti-angiogenesis clinical trials| What is anti angiogenesis treatment? | Lancet Oncol ; Leuk Res ; J Neuropathol Exp Neurol ; A non—RGD-based integrin binding peptide ATN blocks breast cancer growth and metastasis in vivo. Vafopoulou, Polyxeni, Malamati Kourti. |
| Anti-angiogenesis in cancer therapeutics: the magic bullet | Anti-angiogenic drug targets. Monospecific bevacizumab, 2—3-targeted aflibercept and ramucirumab, and multi-targeted tyrosine kinase inhibitor anti-angiogenic drugs are currently used to treat cancer in human patients. VEGF signaling and anti-VEGF drug targets. VEGF stimulates tumor angiogenesis by activating endothelial VEGFR2 and its downstream signaling. Drugs targeting various signaling components have been developed for clinical use. VEGF vascular endothelial growth factor, VEGFR2 vascular endothelial growth factor receptor 2. In contrast to antibody-based and soluble receptor-based biologics, small chemical compound-based drugs are far less specific. The most commonly used tyrosine kinase inhibitors TKIs that block VEGFR-mediated signaling pathways are small chemical molecules targeting a broad spectrum of kinases [ 36 , 37 ]. Most VEGFR-TKIs, including sunitinib, sorafenib, and pazopanib, indistinguishably target VEGFR1, VEGFR2, and VEGFR3 signaling pathways. Additionally, these receptor inhibitors also block many other receptor kinases that are not parts of the VEGFR family but are often related to angiogenic signaling pathways, including members of the platelet-derived growth factor PDGF receptor and fibroblast growth factor FGF receptor families [ 38 ]. Theoretically, anti-angiogenic drugs that target abroad spectrum of signaling pathways would be more desirable and effective for treating cancer since malignant tissues are heterogeneous with different populations of tumor and host cells that produce various angiogenic factors. In this regard, anti-angiogenic TKIs would be more effective than antibody-based and soluble receptor-based drugs that solely target the VEGF pathway. However, clinical experience with anti-angiogenic therapy shows that TKIs may not necessarily be more effective than bevacizumab. Additionally, anti-angiogenic TKIs and bevacizumab show different profiles of toxicity, although both classes of drugs commonly cause some adverse effects. An important difference between biologics and TKIs is that antibody-based drugs have a longer half-life than small chemical molecules. They are inactivated using different metabolic pathways. Anti-angiogenic drugs target tumor blood vessels that exhibit heterogeneity [ 39 ]. However, none of available drugs are specifically delivered to the tumor tissue. They are delivered systemically to cancer patients, exposing all the tissues and organs to the drugs [ 22 ]. Would systemic delivery of anti-angiogenic drugs affect non-tumoral healthy vasculatures? In tumor-free healthy mice, systemic treatment with anti-angiogenic drugs, including an anti-VEGF neutralizing antibody and TKI-targeting VEGFRs, resulted in robust vascular regression in many tissues and organs. In all tissues, vasculatures in endocrine organs, including the thyroid, adrenal gland, ovary, and pancreatic β-islets, underwent robust regression in response to systemic anti-angiogenic therapy [ 40 ]. In addition to changes in vascular density, the endothelia underwent structural changes by replacing fenestrae with the intracellular vesiculo-vacuolar organelles. In normal physiological conditions, VEGF is a crucial hemostatic factor for endothelial cell survival and endothelium fenestrations in endocrine vasculatures. Thus, systemic inhibition of VEGF function would inevitably cause structural changes and decreases in vascular density. The anti-angiogenic drug-induced vascular changes also produce functional alterations in their respective organs. For example, thyroid hormones are significantly decreased after prolonged treatment with anti-VEGF drugs, resulting in hypothyroidism [ 41 ]. In addition to causing changes to the endocrine organs, anti-VEGF drugs also induce rigorous vascular regression in the liver, gastrointestinal wall, and kidney cortex [ 41 ]. Vascular regression inevitably creates a hypoxic environment in the targeted tissues and organs that eventually affects organ functions. These functional changes manifest as clinically adverse effects, such as hypertension, gastrointestinal perforation, hemorrhages, and protein in urine, which are commonly seen in cancer patients who are treated with anti-angiogenic drugs [ 15 , 38 , 42 ]. Paradoxically, off-tumor targets of anti-VEGF drugs can sometimes be beneficial for cancer patients [ 22 ]. This is particularly the case if circulating VEGF expression levels are extremely high in the patients whose tumors produce high amounts of VEGF. For example, in patients with von Hippel—Lindau Vhl gene-mutated renal cell carcinoma, VEGF expression levels can be very high [ 43 ]. Circulating VEGF also causes destructive effects in remote healthy tissues and organs, such as the bone marrow, liver, and spleen [ 44 ]. In this case, inhibition of VEGF-induced vascular impairment would potentially improve patient survival, as shown in preclinical models. An important and clinically practical issue related to anti-angiogenic therapy is length of treatment. How long should a cancer patient be treated with anti-angiogenic drugs? What would happen if anti-angiogenic treatment was discontinued? Currently, no consensus exists regarding treatment timeline with anti-angiogenic drugs. As an anti-angiogenic component is added to the standard chemotherapy regimen, anti-angiogenic therapy follows the timeline of chemotherapy. In clinical practice, anti-angiogenic treatment will inevitably be discontinued. Additionally, anti-angiogenic treatment will likely result in adverse effects that make therapy withdrawal difficult. Similarly, if patients acquire drug resistance during treatment, this can also result in discontinuation of therapy. In animal cancer models, discontinuation of anti-angiogenic therapy resulted in rapid regrowth of tumor blood vessels [ 45 ]. For small chemical compound-based drugs, revascularization occurs 2—3 days after drug withdrawal and reaches a maximal level around day 7. Around this time, revascularization generates a rebound time window that drives angiogenesis to a level higher than it was prior to treatment [ 41 ]. It is possible that rebound angiogenesis reflects the time course of angiogenic vessel growth before vascular remodeling and maturation. Effects of ON and OFF treatment with anti-angiogenic drugs on tumor vasculatures. Rapid revascularization and rebound angiogenesis can occur after treatment is discontinued. It is unclear if, after discontinuation of anti-angiogenic therapy, rebound angiogenesis also occurs in human patients. However, reasonable speculation suggests that human tumors and mouse tumors would respond similarly. If rebound angiogenesis does occur in human cancer patients, discontinuation of anti-angiogenic therapy could potentially result in accelerated tumor growth. Thus, non-stop, lifetime anti-angiogenic treatment should be recommended. In support of this view, prolonged anti-angiogenic therapy has resulted in prolonged survival for human cancer patients. Originally, researchers believed that angiogenesis inhibitors, especially the endogenous inhibitors such as angiostatin, endostatin, and other generic inhibitors, would not develop drug resistance of tumor cells because they target endothelial cells rather than tumor cells [ 46 , 47 ]. Unlike malignant cells, endothelial cells, even those located in tumor tissues, have stable genomes and do not seem to use the canonical drug-resistant mechanisms. However, both experimental and clinical findings have challenged this view. Some studies showed that endothelial cells in angiogenic tumor vessels contain aberrant genomes that would not be present in healthy vasculatures [ 48 ]. It is unclear if the tumor-like aberrant genetic information in endothelial cells is transferred from tumor cells or if the intrinsic development genomic instability develops in endothelial cells. Inhibition of tumor angiogenesis could alter the cellular and molecular components in the tumor microenvironment, leading to development of drug resistance. For example, anti-angiogenic drug—induced vascular regression in the tumors creates tissue hypoxia in a local microenvironment, which augments expression levels of multiple angiogenic factors unrelated to the drug targets [ 36 , 49 ]. Investigators have shown that anti-VEGF drugs develop resistance of tumor cells by this compensatory mechanism. Moreover, anti-VEGF drugs also tip the balance between various cellular compositions, including inflammatory cells and stromal fibroblasts, which are important sources of cytokines and non-VEGF angiogenic factors that contribute to drug resistance [ 50 , 51 ]. Alternative mechanisms of tumor neovascularization that are not affected by drug targets also contribute to anti-angiogenic drug resistance. For example, vessel co-option, vascular mimicry, intussusception, and vasculogenesis support tumor growth and potentially inhibit anti-angiogenic treatment [ 10 , 37 , 52 — 54 ]. In patients who demonstrate intrinsic resistance to anti-VEGF therapy, non-VEGF angiogenic factors probably stimulate angiogenesis in their tumors. Thus, combination therapeutic approaches that target different angiogenesis signaling pathways would likely be more effective. Also, patients who take multi-targeted drugs such as TKIs would be less likely to develop drug resistance. Importantly, cross-communication between different angiogenic signaling pathways can generate synergistic effects, even though expression levels of each individual factor are low. For example, the synergistic effects between FGF receptor 2 and PDGF-BB on angiogenesis promote tumor growth and metastasis [ 55 , 56 ]. In clinical practice, combination therapy represents a major mechanistic challenge [ 57 ]. Why would clinical benefits be achieved by combining anti-angiogenic drugs with chemotherapy? Why would anti-angiogenic treatment alone be sufficiently effective? A few possible hypotheses may explain the mechanism underlying combination therapy. One hypothesis suggests that treatment with anti-angiogenic drugs produces a normalized vascular phenotype, which increases vascular perfusion rather than decreases it [ 58 ]. In the presence of chemotherapeutic agents, increased vascular perfusion enables more cytotoxic drugs to reach the tumors, leading to increased tumor cell death. In other words, when administered with chemotherapeutics, anti-angiogenic treatment inhibits tumor growth. Also, the results of animal tumor models have demonstrated that anti-angiogenic drug-induced vascular normalization occurs within a limited time during treatment i. The mechanism underlying how combination therapy relates to vascular normalization is a paradox. If anti-angiogenic drugs induce vascular normalization and possibly blood perfusion in tumors, tumor growth would be accelerated. However, in both preclinical cancer models and clinical cancer patients, anti-angiogenic treatment does not promote tumor growth, although some researchers have suggested that the treatment facilitates cancer invasion [ 60 , 61 ]. Another experimental study suggested that the mechanism underlying combination therapy can be explained by a decrease of chemotherapeutic toxicity [ 62 ]. Chemotherapeutics produce a broad spectrum of toxicity, including suppression of bone marrow hematopoiesis and high levels of circulating VEGF. Many cancer patients have high levels of circulating VEGF and manifest anemia [ 63 ]. A causal relationship between VEGF and anemia in human cancer patients has yet to be established, but studies of animal cancer models have shown that tumor-derived high-circulating VEGF causes severe anemia [ 44 ]. In high VEGF-producing tumor-bearing mice, chemotherapy and VEGF synergistically suppressed bone marrow hematopoiesis, resulting in early death [ 62 ]. Anti-VEGF treatment ablates VEGF-induced anemia and thus increases tolerance of chemotoxicity. Anti-angiogenic drugs recover bone marrow hematopoiesis prior to chemotherapy and increase tolerance of chemotoxicity [ 62 ]. If this regimen were approved for at least a subset of human cancer patients, it would probably result in substantially increased survival benefits for these patients. Mono-specific anti-VEGF drugs such as bevacizumab target only VEGF without binding to other proteins. VEGF expression levels would serve as a reliable predictive marker for selecting cancer patients who are likely to benefit from anti-VEGF therapy. Based on more than 10 years of clinical experience with various cancer types, simply measuring VEGF expression levels, in either the circulation or tumor biopsies, has not fulfilled the criterion for predicting responders [ 64 — 68 ]. Why would VEGF, as the sole target for bevacizumab, not serve as a reliable predictive marker for patient selection? There is no satisfactory answer to this puzzling question. However, some researchers have suggested that measuring different isoforms of VEGF might more reliably predict responders of anti-VEGF therapy [ 69 — 71 ]. Smaller VEGF isoforms, including VEGF, lack heparin-binding affinity and diffuse distally from their productive sites. Additionally, proteolytically processed smaller versions of VEGF can also lack high heparin-binding affinity and can be transported to distal tissues and organs. Interestingly, these small versions of VEGF proteins have some predictive values, although their targets may not be limited to tumor tissues. It is possible that off-tumor targets of these small VEGF proteins predict their therapeutic values [ 22 ]. Indeed, based on preclinical and clinical findings, the potentially beneficial effects of anti-VEGF drug off-tumor targets have been proposed [ 22 ]. Many physiological, cellular, and molecular biomarker candidates related to anti-angiogenic therapy-induced adverse effects have been proposed, but in clinical practice physiological responses are the most commonly used biomarkers. For example, anti-angiogenic drug-induced hypertension has been associated with clinical benefits; however, the molecular mechanism underlying the benefit is unknown [ 72 — 78 ]. Given that adding anti-angiogenic components to conventional chemotherapy is widely used for the treatment of cancer, significant clinical benefits without selection biomarkers are truly valuable. Assuming a reliable predictive biomarker exists, treating a selected population of responders with anti-angiogenic drugs would likely markedly increase clinical benefits. Future efforts should focus on identifying such a reliable biomarker for clinical use. Systemic delivery of anti-angiogenic drugs to cancer patients would inevitably expose non-cancerous healthy tissues to these drugs [ 40 , 41 ]. In preclinical studies, investigators have shown that systemic treatment induces vascular changes in multiple tissues and organs. Additionally, anti-VEGF therapy caused a marked reduction in micro vasculatures in the liver, kidney, and gastrointestinal wall [ 40 , 41 ]. Vascular changes in non-tumor tissues are associated with clinical adverse effects, including hypertension, hypothyroidism, gastrointestinal perforation, and cardiovascular disease [ 15 , 79 ]. Since VEGF is an important hemostatic factor for maintaining the number and structure of microvessels in various tissues and organs, it is perhaps not surprising that anti-VEGF-based anti-angiogenic drugs would cause broad adverse effects. How would anti-angiogenic drugs be directly delivered to tumorous tissues without affecting the healthy vasculature? Designing a new generation of targeted drugs would be a very challenging task. Even though anti-angiogenic drugs are locally injected into tumorous tissues, they still enter the circulation. Additionally, this approach would prevent anti-angiogenic agents from reaching metastatic tumors. In fact, clinical indications of using anti-angiogenic therapies approved by the U. FDA often include metastatic disease. Inhibition of angiogenesis for the treatment of cancer has been successfully translated into clinical use. The key issue is that patients who receive anti-angiogenic drugs experience relatively few clinical benefits. For patients with some cancer types, including pancreatic cancer and breast cancer, the addition of an anti-angiogenic component to chemotherapy has not produced meaningful improvement in overall survival. If all solid tumor growth depends on angiogenesis, why would anti-angiogenic treatments not be beneficial? Why would anti-angiogenic monotherapies fail to demonstrate clinical benefits? What is the mechanistic rationale of combination therapy with chemotherapeutics? Could a predictive marker be identified? How long should cancer patients be treated with anti-angiogenic drugs? What could happen if the anti-angiogenic therapy is discontinued? Would combinations of drugs that target different angiogenic pathways improve therapeutic outcomes? There are no unified opinions on these clinical issues. Possibly, an important means to address these issues is to establish clinically relevant cancer models in animals. Given sophisticated cancer biology, metastatic disease, and systemic disorders in cancer patients, the complex mechanisms underlying malignant disease cannot likely be simply explained. The same type of cancer in different patients may represent a different disease. Likewise, the same cancer in the same patient may represent a different disease at different stages of progression. This means that personalized medicine may not be sufficiently effective and that dynamic approaches should be developed for treating cancer at different stages during disease development. In clinical practice, developing both personalized therapy and dynamic therapy is an extremely challenging task. Forty-year journey of angiogenesis translational research. Sci Transl Med. Article PubMed Google Scholar. Folkman J. 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You can also search for this author in PubMed Google Scholar. SQ and AL performed the selection of literature, drafted the manuscript, and prepared the figures. MY and SY collected the related references. MZ participated in the design and discussion. KW carried out the design of this review and revised the manuscript. All authors contributed to this manuscript. All authors read and approved the final manuscript. Correspondence to Kongming Wu. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Qin, S. et al. Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol 12 , 27 Download citation. Received : 21 January Accepted : 05 March |
| Angiogenesis Inhibitors - NCI | Folkman, J. Google Scholar Meert A-P, Paesmans M, Martin B, Delmotte P, Berghmans T, Verdebout J-M, et al. If all solid tumor growth depends on angiogenesis, why would anti-angiogenic treatments not be beneficial? Received : 18 November Article PubMed Google Scholar Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. An important family of proteinases essential for the degradation of the extracellular matrix ECM and the basement membrane during angiogenesis include the family of matrix metalloproteinases MMPs Liotta and Stetler-Stevenson, |
Anti-angiogenesis clinical trials -
The results of this phase III randomized trial showed that the addition of bevacizumab to capecitabine in second-line therapy improved response rate compared to capecitabine treatment alone However, this combination neither improved progression-free survival PFS median, 4. The E was an open-label, randomized, phase III clinical trial that investigated the efficacy and safety of the combination of paclitaxel and bevacizumab compared to paclitaxel as a first-line treatment for metastatic breast cancer Miller et al.
Findings from the E trial indicated a significantly improved PFS for the combination arm compared to paclitaxel alone, while OS was similar in both treatment arms median, The results from the AVFG and E trials granted accelerated approval of bevacizumab use in the treatment of metastatic breast cancer by the US Food and Drug Administration FDA.
Subsequently, several phase III clinical trials have evaluated bevacizumab with chemotherapy revealing no significant improvement in OS Miles et al. The failure of achieving a survival advantage along with serious tolerability issues created controversy over the real value of bevacizumab treatment in metastatic breast cancer and further brought its approval into question.
Ultimately, the US FDA had revoked the indication of bevacizumab to treat patients with metastatic breast cancer in Sasich and Sukkari, After the withdrawal statement, results from other clinical trials on the use of bevacizumab in breast cancer were published.
The BEATRICE study was an open-label, randomized, phase III clinical trial that assessed the addition of bevacizumab to chemotherapy in adjuvant settings in patients with operable TNBC Cameron et al. Results from the BEATRICE study revealed no improvement of OS compared to patients receiving chemotherapy alone Cameron et al.
Rather, grade III adverse events were increased in the bevacizumab arm Cameron et al. The E study was a double-blind, phase III trial of adjuvant chemotherapy with and without bevacizumab in breast cancer patients with lymph node-positive and high-risk lymph node-negative disease Miller et al. The findings of the study failed to show improvements in invasive disease-free survival or OS upon the addition of bevacizumab to chemotherapy in adjuvant settings in breast cancer patients with high-risk HER2-negative disease Miller et al.
Other studies investigated the value of adding bevacizumab to chemotherapy in the neoadjuvant treatment of breast cancer Bear et al. The primary endpoint in these studies was the pathologic complete response pCR rate.
Overall, findings from these clinical trials showed a favorable response for using bevacizumab with chemotherapy in neoadjuvant treatment in terms of increased pCR rates Bear et al. Recently, Martin et al. examined the addition of bevacizumab to endocrine drugs as first-line treatment in metastatic hormone receptor-positive breast cancer through pooled data analysis from the LEA and CALGB trials Martin et al.
The addition of bevacizumab significantly improved PFS compared to endocrine treatment alone, however, there was no difference in OS between both groups. Besides, a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC was conducted by Symonds et.
Symonds et al. No significant difference was seen for either PFS or OS for patients enrolled and none of them achieved complete response Symonds et al. Ramucirumab Cyramza ® is a monoclonal antibody targeting VEGFR-2 Singh and Parmar, It was first approved by the US FDA in as monotherapy for the treatment of metastatic gastric cancer Casak et al.
Ramucirumab approval was thereafter expanded to combination treatment with chemotherapy for gastric cancer, non-small cell lung cancer NSCLC , and colon cancer. The drug is also approved as monotherapy for hepatocellular carcinoma HCC , and most recently in combination with erlotinib for patients with epidermal growth factor receptor EGFR -positive NSCLC Effing and Gyawali, Few clinical trials investigated ramucirumab treatment in breast cancer.
In phase II, randomized, open-label study, the addition of ramucirumab to capecitabine in previously treated patients with locally advanced and metastatic breast cancer failed to improve PFS and OS compared to capecitabine therapy alone Vahdat et al.
The frequency of adverse effects was increased in the combination group and included headache, anorexia, constipation, epistaxis, and hypertension Vahdat et al.
Another phase II, randomized, open-label clinical trial revealed no difference in survival for the combination of ramucirumab and eribulin versus eribulin monotherapy in patients with advanced breast cancer Yardley et al.
In agreement with findings from previous phase II trials, ramucirumab neither improved PFS nor OS compared to docetaxel treatment median, 9. Higher rates of toxicity were reported in patients receiving ramucirumab treatment Mackey et al.
Tyrosine kinase inhibitors TKIs are small molecules that inhibit the kinase domain of RTKs thus inhibiting receptor activation and downstream signaling Fakhrejahani and Toi, Several angiogenesis inhibitors are small-molecule TKIs.
Sorafenib Nexavar ® is an oral multikinase inhibitor of VEGFR, PDGF receptor PDGFR , and Raf Ben Mousa, The drug is approved for the treatment of renal cell carcinoma RCC Kane et al. The use of sorafenib in breast cancer showed modest efficacy in early clinical trials.
In a randomized, double-blind, placebo-controlled, phase IIb trial, the addition of sorafenib to capecitabine showed higher toxicity and no improvement in OS in patients with locally advanced or metastatic HER2-negative breast cancer Baselga et al.
In another phase IIb, double-blind, randomized, placebo-controlled study, the addition of sorafenib to capecitabin or gemcitabine moderately improved PFS compared to placebo and chemotherapy in breast cancer patients median, 3.
Nevertheless, no significant effect was observed for OS for patients in the sorafenib arm Schwartzberg et al. Despite the modest effects for sorafenib treatment observed in terms of improved PFS, subsequent clinical trials failed to confirm the survival advantage for the drug in breast cancer treatment.
Nevertheless, rates of grade III toxicities were notably higher in the sorafenib arm Baselga et al. In the PASO trial, the safety and efficacy of adding sorafenib to paclitaxel compared to paclitaxel alone were assessed in an open-label, randomized, phase II study design in patients with locally advanced or metastatic HER2-negative breast cancer Decker et al.
Interestingly, a pre-planned efficacy interim analysis showed that patients on paclitaxel monotherapy had a significantly greater PFS and OS compared to patients in the combination arm. Toxicities were higher in the combination arm and the study was therefore discontinued Decker et al.
Similarly, results from the MADONNA study, a multicenter, double-blind, phase II study, revealed a lack of survival advantage upon the addition of sorafenib to docetaxel as first-line treatment in breast cancer patients with metastatic or locally advanced HER2-negative disease Mavratzas et al.
Recently, Ianza et al. showed no difference in survival outcomes for adding sorafenib to letrozole and cyclophosphamide in postmenopausal patients with locally advanced estrogen receptor ER -positive, HER2-negative breast cancer in a phase III trial Ianza et al.
Interestingly, a higher percentage of patients on sorafenib treatment had disease progression Ianza et al. Other clinical studies have constantly supported a lack of survival advantage for the combination of sorafenib and chemotherapy in patients with advanced breast cancer Gradishar et al.
Sunitinib Sutent ® is a novel oral multitargeted TKI of VEGFR-1, VEGFR-2, fetal liver tyrosine kinase receptor 3, c-KIT, PDGFR-α, and PDGFR-β Le Tourneau et al. Sunitinib is FDA approved for the treatment of advanced RCC, gastrointestinal stromal tumors Le Tourneau et al.
Clinical studies for the efficacy of sunitinib in breast cancer treatment have produced disappointing results Yardley et al. In , a multicenter, randomized, open-label, phase III trial was conducted to assess the effect of sunitinib versus capecitabine as a treatment for advanced breast cancer patients with disease recurrence after anthracycline and taxane therapy Barrios et al.
Compared to the capecitabine arm, PFS and OS were shorter for sunitinib median, 2. Sunitinib treatment was also associated with a higher rate and severity of adverse events compared with capecitabine.
Bergh et al. demonstrated no improvement in PFS or OS in breast cancer patients treated with the combination of sunitinib and docetaxel compared to docetaxel alone in an open-label, randomized, phase III trial Bergh et al. Moreover, more adverse events, deaths, and treatment discontinuations were observed in the combination arm Bergh et al.
In a randomized, phase II trial comparing sunitinib to the standard of care in patients with TNBC who relapsed after anthracycline- and taxane-based chemotherapy, no difference between both treatment arms for PFS and OS was observed Curigliano et al. In a randomized, phase III study by Crown et al.
The combination arm failed to improve therapeutic outcomes compared to the capecitabine arm as no statistically significant difference was observed for PFS median, 5.
Vandetanib Caprelsa ® is an oral small-molecule inhibitor of VEGFR-2, VEGFR-3, EGFR, and RET Chau and Haddad, It is approved for the treatment of medullary thyroid carcinoma Chau and Haddad, The efficacy and safety of vandetanib with docetaxel as a second-line treatment for advanced breast cancer was assessed in a double-blind, placebo-controlled, randomized, phase II study Boer et al.
Though well-tolerated, the combination of vandetanib and docetaxel did not improve outcomes compared to placebo and docetaxel Boer et al.
Clemons et al. also showed no difference in PFS or OS for the combination of vandetanib and fulvestrant compared to placebo in postmenopausal patients with metastatic breast cancer in a phase II trial Clemons et al.
Axitinib Inlyta ® is an oral second-generation pan-VEGFR TKI Bellesoeur et al. The drug is approved for the treatment of advanced RCC Tyler, Rugo et al. assessed the efficacy of axitinib plus docetaxel compared to docetaxel and placebo in metastatic breast cancer in a randomized, double-blind, phase II study Rugo et al.
The addition of axitinib to capecitabine did not significantly improve time to progression compared to the placebo arm median, 8. Pazopanib Votrient ® is an oral multitarget TKI of VEGFR, PDGFRs, FGFR, and c-KIT Lee et al. It is approved for the treatment of advanced RCC and advanced soft-tissue sarcoma Nguyen and Shayahi, In , results from a phase II study of single-agent pazopanib in patients with recurrent or metastatic breast cancer revealed promising activity in terms of disease stability and tolerable adverse events Taylor et al.
Nevertheless, subsequent phase II trials for the combination of lapatinib and pazopanib in HER2-positive breast cancer failed to show survival advantage compared to lapatinib alone. The combination also had increased toxicity compared to lapatinib monotherapy Cristofanilli et al.
The addition of pazopanib to chemotherapy in neoadjuvant treatment for HER2-negative locally advanced breast cancer was assessed in a phase II study, however substantial toxicity resulted in a high discontinuation rate of pazopanib Tan et al.
Cediranib Recentin ® is a pan-VEGFR inhibitor Tang et al. It has been assessed in combination with hormonal treatments in breast cancer patients. A randomized, phase II study evaluated cediranib plus fulvestrant in postmenopausal women with hormone-sensitive metastatic breast cancer compared to placebo Hyams et al.
The addition of cediranib to fulvestrant did not improve median PFS versus placebo. Furthermore, the rates of grade III adverse events, discontinuations, and dose reductions were higher in the cediranib arm Hyams et al.
The available experimental evidence, which is not yet definitive, proposes several distinct mechanisms that manifest tumor rescue pathways to anti-angiogenic therapies. Several mechanisms for intrinsic and acquired resistance to angiogenesis inhibitors have now been explored.
Some of these mechanisms are discussed below. The activation of compensatory pro-angiogenic pathways in response to anti-VEGF therapy is a well-established mechanism of acquired resistance in tumors Bergers and Hanahan, ; Ramadan et al. Typically, vasculogenesis is a minor pathway in the development of tumor vasculature at which angiogenesis is the primary pathway.
However, upon the inhibition of angiogenic growth, vasculogenesis may become crucial to maintaining tumor vasculature Brown, Hypoxia-induced by anti-VEGF therapy leads to the recruitment of pro-angiogenic bone marrow-derived cells BMDCs to the tumor microenvironment Lord and Harris, ; Ramadan et al.
BMDCs can restore vascularization of tumors thus enabling them to overcome hypoxia and become resistant to anti-VEGF drugs Bergers and Hanahan, ; Lord and Harris, Several BMDCs have been identified in the tumor microenvironment such as tumor-associated macrophages TAMs , pro-angiogenic monocytic cells, myeloid cells, and Tieexpressing macrophages Lord and Harris, TAMs were associated with high VEGF expression and high microvessel density in ductal breast carcinoma Longatto Filho et al.
Tripathi et al. revealed that TAMs were recruited to tumor microenvironment in an animal model of breast cancer by eotaxin and oncostatin M cytokines Tripathi et al. Blocking these cytokines with neutralizing antibodies reduced tumor vascularization and improved sensitivity to bevacizumab Tripathi et al.
Liu et al. Obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors in murine breast cancer model Incio et al. Inhibition of IL-6 normalized tumor vasculature, reduced hypoxia, and restored sensitivity to anti-VEGF therapy.
Heterogeneous pericyte coverage has been described in several types of tumors, at different stages of tumor progression, and even within a single tumor stage Hida et al. The reduction in tumor vascularity induced by anti-VEGF therapy enhances the recruitment of pericytes to maintain blood vessel function and integrity Bergers and Hanahan, Increased pericyte coverage of these blood vessels supports tumor endothelium to survive and function despite the anti-angiogenic drug Bergers and Hanahan, ; Lord and Harris, In addition, pericytes can release pro-angiogenic factors in response to PDGF Lord and Harris, In the breast cancer vasculature, heterogenous pericyte coverage was identified Kim et al.
However, the impact of pericyte on resistance to anti-VEGF therapy in breast tumors is largely unknown. Vasculogenic mimicry and vessel co-option may decrease the dependence on classical angiogenesis by tumors Schneider and Miller, ; Bergers and Hanahan, ; Carmeliet and Jain, These alternative mechanisms render tumors insensitive to anti-angiogenic agents by allowing tumors to obtain the necessary blood supply when classical angiogenesis is limited Schneider and Miller, ; Haibe et al.
Vasculogenic mimicry is associated with aggressive breast cancer phenotypes and poor prognosis Shen et al. Bevacizumab failed to inhibit vasculogenic mimicry in the HCC breast cancer cell line Dey et al. Besides, Sun et al.
showed that the administration of sunitinib induced vasculogenic mimicry in animal models of TNBC which ultimately promoted resistance to sunitinib therapy Sun et al.
Vascular co-option is another mechanism to escape angiogenesis inhibitors and has been shown to drive brain metastasis of breast cancer cells Ramadan et al.
Growing evidence supports the concept of the heterogeneity of the endothelium of vessels involved in angiogenesis Hida et al. Hida et al. showed that tumor blood vessels are heterogeneous and that tumor-associated endothelial cells had relatively large, heterogeneous nuclei, cell aneuploidy, and chromosomal alterations indicative of cytogenetic abnormalities Hida et al.
Altered gene and protein expression profiles in tumor endothelium have also been reported Aird, The heterogeneity of tumor endothelial cells may differ by tumor type, tumor microenvironment, and the stage of tumor growth Hida et al. Grange et al. showed that breast cancer-derived endothelial cells did not undergo normal cell senescence in culture, had increased motility, and constantly expressed markers of endothelial activation and angiogenesis Grange et al.
These endothelial cells were resistant to the cytotoxic activity of chemotherapeutic drugs as compared to normal micro-endothelial cells Grange et al. The functional abnormalities of tumor-associated endothelial cells and the microvascular heterogeneity could explain, at least in part, the reduced efficacy of anti-angiogenic therapy in breast cancer by enabling endothelial cells an increased pro-angiogenic activity to acquire drug resistance Grange et al.
Lack of response to angiogenesis inhibitors may be explained in terms of the stage of progression, treatment history, and genomic constitution that exist in the tumor microenvironment Bergers and Hanahan, An analysis of human breast cancer biopsies demonstrated a plethora of pro-angiogenic factors in late-stage breast cancers including FGF-2, in contrast to earlier-stage tumors which preferentially expressed VEGF Relf et al.
Thus, resistance to anti-VEGF drugs in advanced-stage breast cancer may be explained by the dominance of FGF-2 and other pro-angiogenic factors in such stage of the disease Bergers and Hanahan, Invasive cancers commonly express multiple angiogenic factors and this heterogeneity occurs at an early point in time.
Genetic instabilities in the tumor cells may cause alterations of both the amount and type of pro-angiogenic factors expressed in a tumor which could further promote resistance to anti-angiogenic treatments Schneider and Miller, Cancer stem cells are a subpopulation of cancer cells capable of self-renewal, differentiation, and induction of tumorigenesis, metastasis, and drug resistance Li et al.
The potential of cancer stem cell trans-differentiating into endothelial cells has been reported in a variety of solid tumors Li et al. Bussolati et al. showed that breast cancer stem cells were able to differentiate into the endothelial lineage in the presence of VEGF Bussolati et al.
The stem cells acquired several endothelial markers and organized into capillary-like structures forming vessels in a xenograft animal model Bussolati et al.
Similarly, Wang et al. showed that breast cancer stem cells may trans-differentiate into endothelial cells that can form capillary-like vascular structures in the cell culture system and participate in tumor angiogenesis Wang et al.
An earlier study demonstrated that microRNAa miRNAa expression promoted tumor angiogenesis and metastasis in vivo by mediating endothelial trans-differentiation of breast cancer stem-like cells Tang et al.
Brossa et al. reported the ability of breast cancer stem cells to trans-differentiate to endothelial cells expressing endothelial markers under hypoxic conditions in vitro Brossa et al.
Notably, treatment with the VEGFR inhibitor sunitinib but not the VEGF inhibitor bevacizumab impaired the endothelial differentiation ability of breast cancer stem cells both in vitro and in vivo.
Mechanistically, sunitinib, but not bevacizumab, suppressed HIF-1α required for endothelial differentiation under hypoxic conditions Brossa et al. Together, increasing evidence suggests that cancer stem cell endothelial trans-differentiation supports tumor vascularization and partly contributes to the failure of anti-angiogenic drugs.
The lack of efficacy of the conventional angiogenesis inhibitors necessitates exploring novel angiogenic pathways in breast cancer. Given the heterogeneity of breast cancer and the complexity of angiogenesis, it is unlikely that the identification of a single target such as VEGF would be adequate in the treatment of this disease.
Interleukins ILs are a family of cytokines known to play essential roles in the regulation of several immune cell functions such as differentiation, activation, proliferation, migration, and adhesion Turner et al. Interactions of ILs and their receptors in endothelial cells have been shown to regulate angiogenesis through pro-angiogenic and anti-angiogenic activity Ribatti, Serum IL-6 levels were elevated in breast cancer patients compared to controls Barron et al.
Additionally, serum IL-6 and VEGF correlated positively in breast cancer patients Raghunathachar Sahana et al. Higher expression of IL-6R was demonstrated in clinical specimens for patients with high-grade invasive ductal carcinoma Bharti et al.
A recent study by Hegde et al. showed that a crosstalk between IL-6 and VEGFR-2 signaling pathways exists in myoepithelial and endothelial cells isolated from clinical human breast tumors Hegde et al.
IL-6 epigenetically regulated VEGFR-2 expression through induction of proteasomal degradation of DNA methyltransferase 1 leading to promoter hypomethylation and angiogenic activity Hegde et al.
IL-8 is a pro-inflammatory cytokine that exerts its biologic activity through binding to its CXCR1 and CXCR2 receptors Waugh and Wilson, IL-8 enhanced the proliferation of cancer cells and produced a pro-angiogenic activity Waugh and Wilson, Serum IL-8 levels were significantly higher in breast cancer patients compared with healthy subjects and were associated with advanced disease Benoy et al.
High levels of IL-8 are secreted by stromal cells into the microenvironment of breast cancer patients compared to controls Razmkhah et al. Evidence from preclinical studies showed that IL-8 mediated invasion and angiogenesis of breast cancer cells Lin et al.
Cancer-associated adipocytes express high levels of IL-8 in breast cancer stroma thus promoting the pro-angiogenic effects of breast adipocytes Al-Khalaf et al. In this context, ILexpressing adipocytes increased vascularity of tumor xenografts as indicated by increased expression of CD34, an endothelial cell marker Al-Khalaf et al.
Neutralization of IL-8 or inhibiting its target receptors had been shown to reduce breast cancer growth and angiogenesis Lin et al.
Nannuru et al. showed that silencing of CXCR2 expression reduced tumor vascularity and inhibited spontaneous lung metastasis in an orthotopic animal model of breast cancer Nannuru et al.
Further, CXCR1 blockade with the small molecule inhibitor, repertaxin reduced metastasis in an animal model of breast cancer Ginestier et al. The platelet-derived growth factor PDGF family consists of four gene products PDGF-A, -B, -C, and -D that are combined into five different isoforms: PDGF-AA, -BB, -CC, -DD, and -AB Bartoschek and Pietras, These factors bind and activate their respective RTKs, PDGFR-α, and PDGFR-β.
PDGF family plays a key role in a wide range of oncologic activities essential for cancer growth including angiogenesis, fibrosis, and cellular migration Bartoschek and Pietras, High expression of PDGFs was correlated with an advanced presentation, increased recurrence, and poor survival in patients with invasive breast cancer Jansson et al.
PDGF is an important regulator for the motility of vascular smooth muscle cells induced by breast cancer cells Banerjee et al. Besides, the expression of HIF-1α in invasive breast cancer was significantly associated with angiogenesis and expression of PDGF-BB Bos et al.
Earlier evidence showed that PDGFRs are expressed by breast cancer cells and endothelial cells in metastatic bone lesions in animal models Lev et al. Imatinib remarkably inhibited PDGFR activation in breast cancer cells and tumor-associated endothelial cells and reduced microvessel density in the tumors Lev et al.
Recently, Wang et al. provided evidence from cell culture and animal studies that the downregulation of PDGF-B greatly contributed to the metformin-induced vessel normalization in breast cancer Wang et al.
Fibroblast growth factors FGFs belong to a large family of growth factors that includes 23 members Hui et al. FGFs are key regulators of numerous physiological processes such as angiogenesis, wound healing, and embryonic development. These functions are mediated by the binding of FGFs with their receptors FGFRs , which belong to the RTK family Hui et al.
Growing evidence signifies the oncogenic impact of FGFs and FGFRs to promote cancer development and progression by mediating cancer cell proliferation, survival, epithelial-to-mesenchymal transition, invasion, and angiogenesis Wesche et al.
Chen et al. showed that dipalmitoylphosphatidic acid, a bioactive phospholipid, induced anti-angiogenic activity, and inhibited tumor growth in an experimental xenograft model of breast cancer Chen J. These effects were attributed to transcriptional inhibition of FGF-1 expression leading to the downregulation of HGF Chen J.
In the same context, Cai et al. showed that neutralizing FGF-2 by a disulfide-stabilized diabody inhibited tumor growth and angiogenesis in a mouse model of breast cancer Cai et al. The antitumor activity was associated with a significant decrease in microvessel density and the number of lymphatic vessels Cai et al.
Formononetin, an FGFR-2 inhibitor, demonstrated anti-angiogenic activity in breast cancer in both ex vivo and in vivo angiogenesis assays Wu et al. Besides, formononetin significantly inhibited angiogenesis in vivo by reducing microvessel density and phosphorylated FGFR-2 levels in tumor tissue Wu et al.
Recent evidence showed that FGFpositive tumors are resistant to clinically available drugs targeting VEGF and PDGF Hosaka et al. The resistance is mediated by the ability of FGF-2 to recruit pericytes onto tumor microvessels through a PDGFR-β-dependent mechanism in breast cancer and fibrosarcoma models.
Dual targeting of the VEGF and PDGF produced a superior antitumor effect in FGFpositive breast cancer Hosaka et al. Angiopoietins Angs represent an imperative family of vascular growth factors that produce their biological effects through binding to the RTKs, Tie-1, and Tie-2 Akwii et al.
Angiopoietin-1 Ang-1 and angiopoietin-2 Ang-2 are best characterized for their role in angiogenesis and vascular stability Akwii et al. Ang-1 regulates the organization and maturation of newly formed blood vessels and promotes quiescence and structural integrity of vasculature Brindle et al.
Alternatively, Ang-2 antagonizes the effects of Ang-1 resulting in vessel destabilization Brindle et al. Ramanthan et al. indicated that high Ang-2 gene expression in breast cancer patients was associated with reduced survival Ramanathan et al.
In addition, a strong correlation existed between Angs and VEGF genes in breast cancer tissues Ramanathan et al.
Besides, serum levels of Ang-2 were significantly higher in breast cancer patients compared to healthy control subjects. High Ang-2 serum levels had shorter survival than that of the low Ang-2 expression group Li et al.
Evidence from preclinical models also demonstrated that Ang-2 mediated initial steps of breast cancer metastasis to the brain Avraham et al.
He et al. showed that targeting Ang-2 with miRNAp reduced tumor growth, angiogenesis, and metastasis in animal models He et al. Besides, Wu et al. showed that oral administration of methylseleninic acid reduced microvessel density and increased pericytes coverage by inhibiting Ang-2 in a breast cancer animal model Wu et al.
Dual inhibition of VEGF-A and Ang-2 using a bispecific antibody promoted vascular regression and normalization in a model of metastatic breast cancer Schmittnaegel et al.
Dual inhibition of Ang-1 and TGF-βR2 was also shown to suppress tumor angiogenesis in breast cancer in vivo Flores-Perez et al.
Notch receptors belong to a highly conserved signaling pathway that relies on cell-cell contacts to mediate a response to environmental signals in multicellular animals Aster et al. Four different Notch receptors are expressed in humans, each is encoded by a different gene. In addition, four functional Notch ligands exist and belong to two families: members of the Delta family of ligands; Dll-1 and Dll-4, and members of the Serrate family of ligands; Jag-1 and Jag-2 Aster et al.
In breast cancer, Notch signaling promotes cell proliferation, self-renewal, anti-apoptotic effects, and angiogenesis Aster et al. Notch expression has been associated with the progression and recurrence of breast cancer Mollen et al.
Proia et al. showed that blocking Notch-1 function with a specific antibody inhibited functional angiogenesis and breast cancer growth in animal models Proia et al. HGF is a member of the plasminogen-related growth factor group and is a known angiogenic factor Nakamura and Mizuno, It is primarily expressed and produced by stromal cells, such as fibroblasts in mammary tissues Jiang et al.
The angiogenic actions of HGF are mediated by binding to its RTK, MET on endothelial cells Organ and Tsao, ; Zhang et al. In the activated endothelial cells, MET is upregulated thus modulating cell dissociation, motility, proliferation, and invasion Peruzzi and Bottaro, HGF regulates VEGF expression in tumor cells promoting angiogenic activity Matsumura et al.
Earlier studies showed that targeting HGF with retroviral ribozyme transgene or HGF antagonist reduced the growth and angiogenesis of breast tumors in vivo Jiang et al. Syndecans are transmembrane proteoglycans composed of a core protein and a glycosaminoglycan side chain to which growth factors are attached Szatmari and Dobra, Syndecan-1 is the major syndecan found in epithelial malignancies Szatmari and Dobra, Syndecan-1 ligates with several pro-angiogenic factors such as VEGF, FGFs, Wnt, and HGF, which act as signaling co-receptors Szatmari and Dobra, Expression of syndecan-1 in breast tumors was associated with adverse prognosticators, metastasis, and reduced OS in patients Kind et al.
Besides, stromal syndecan-1 expression increased vessel density and area and promoted the growth and angiogenesis of triple-negative tumors in vivo Maeda et al.
Schönfeld et al. showed that targeting syndecan-1 with an antibody-drug conjugate reduced the growth of TNBC in animal models when combined with chemotherapy Schonfeld et al. An open-label, phase Ib trial evaluating antitumor activity and safety of erdafitinib; a potent and selective pan-FGFR inhibitor, in combination with fulvestrant and palbociclib in patients with metastatic breast cancer is currently recruiting patients NCT The primary objective is to determine safety and tolerability for the combination treatment of erdafitinib with targeted treatments.
Futibatinib is an orally available pan-FGFR inhibitor that is currently being evaluated in a phase II trial as monotherapy and in combination with fulvestrant in patients with locally advanced or metastatic breast cancer harboring FGFR gene amplification NCT The primary outcome of the trial is to determine dose-limiting toxicities during the first two cycles of therapy while secondary outcomes involve the identification of treatment-emergent adverse events TEAEs and objective tumor response.
Rogaratinib is another novel pan-FGFR inhibitor. Rogaratinib showed broad antitumor activity in preclinical studies Grunewald et al. The combination of rogaratinib plus palbociclib and fulvestrant is being assessed in an open-label, multicenter, prospective, phase I dose-escalation clinical trial NCT The primary aims of the study are to assess the recommended phase II dose and the incidence of TEAEs for the combination treatment in patients with metastatic hormone receptor-positive breast cancer who have FGFR-positive tumors.
Additionally, a phase II study is assessing the long-term efficacy and tolerability of rogaratinib in patients who have received the drug in a previous clinical trial and are currently in the continuation phase NCT The selective FGFR-2 inhibitor, RLY, is being evaluated for tolerability and antineoplastic activity in several advanced solid cancers, including the breast NCT The primary outcomes of the study are to determine the maximum tolerated dose of pemigatinib and to assess the pharmacodynamics of the drug.
The I-SPY 2 trial is investigating the effect of trebananib alone or in combination with standard targeted treatments in neoadjuvant settings in patients with breast cancer NCT The main outcome of the trial is to determine the safety and tolerability of NT-I7 in combination with pembrolizumab.
Bintrafusp alfa is a first-in-class bifunctional fusion protein targeting TGF-β and programmed death-ligand 1 PD-L1 Paz-Ares et al. Furthermore, bintrafusp alfa is being assessed as monotherapy in phase II, multicenter, open-label study in participants with TNBC NCT PF, an inhibitor of TGF-βR1, is being evaluated in a phase I dose-escalation study for its safety, tolerability, and pharmacokinetics in patients with advanced solid tumors NCT Table 2 summarizes ongoing clinical trials for selected non-VEGF angiogenic inhibitors in breast cancer.
TABLE 2. Therefore, exploring novel anti-angiogenic therapeutic approaches is of paramount importance for the treatment of aggressive and advanced breast tumors. Such approaches include vascular normalization by targeting pericytes, utilization of miRNAs and extracellular tumor-associated vesicles, using immunotherapeutic drugs, and nanotechnology.
A potential strategy to sensitize tumor endothelium to angiogenesis inhibitors is by targeting pericytes to achieve tumor vascular normalization Lord and Harris, ; Meng et al. Normalization of tumor vasculature prevents cancer cell metastasis, improves the delivery of systemic anticancer therapies, increases the efficacy of local therapies, and enhances recognition by the host immune system.
Pericyte coverage of tumor blood vessels is heterogeneous. In certain tumors, high pericyte coverage of the tumor vasculature causes resistance to anti-angiogenic therapies.
Alternatively, low pericyte coverage detected in the vasculature of certain tumors reduces vascular stability and increases vascular permeability which impairs the delivery of anticancer therapies to tumor cells and allows them to metastasize Meng et al. Earlier studies showed that combining VEGFR and PDGFR inhibitors targeting endothelial cells and pericytes, respectively, improved the efficacy of anti-angiogenic therapy and reduced tumor growth in animal tumor models Bergers et al.
In a xenograft model of breast carcinoma, tumor vascularization was enhanced by increasing the pericyte-endothelium association via a mechanism involving the TGF-β-fibronectin axis Zonneville et al.
In addition, Keskin et al. showed that pericyte targeting in established mouse breast tumors increased Ang-2 expression and that targeting Ang-2 signaling along with pericyte depletion restored vascular stability and decreased tumor growth and metastasis Keskin et al.
Although data from preclinical studies showed that pericyte targeting could be a novel strategy to normalize tumor vasculature, this strategy should be carefully considered as lack of pericyte coverage may disrupt vascular integrity and promote cancer metastasis Lord and Harris, ; Zirlik and Duyster, Assessment of pericyte coverage of tumor vasculature and the identification of the appropriate pericyte-targeted therapy are potential challenges to pericyte targeting Meng et al.
MicroRNAs miRNAs are critical regulators of signaling pathways involved in angiogenesis and cancer metastasis by interacting with the target mRNAs Gallach et al.
To date, there are groups of well-characterized miRNAs implicated in regulating endothelial cell function and angiogenesis, making them attractive targets in tumor angiogenesis Gallach et al. Liang et al. showed that miRNA suppressed breast tumor angiogenesis through targeting HIF-1α and Ang-1 in breast cancer cell lines and animal model.
MiRNA inhibited the proliferation, migration, and tube formation of endothelial cells and decreased the microvessel density Liang et al. Lu et al. reported that miRNAp inhibited tumor invasion and angiogenesis by silencing VEGF-A in breast cancer cells both in vitro and in vivo Lu et al.
MiRNAb inhibited proliferation, migration, and tube formation of endothelial cells. Systemic administration of miRNAb potently suppressed breast tumor growth and vascularization by targeting Akt and downregulating VEGF and c-Myc in breast cancer cells Li et al.
Mimics of miRNA suppressed the proliferation and tube formation of endothelial cells in vitro Wu et al. Moreover, the overexpression of miRNA reduced VEGF and HIF-1α protein levels and suppressed angiogenesis in vivo Wu et al.
Zou et al. showed that miRNA inhibited growth and angiogenesis of TNBC in vivo via post-transcriptional regulation of N-Ras and VEGF Zou et al. Importantly, miRNAs can be transported between cancer cells and stromal cells through extracellular vesicles known to mediate cell-to-cell communication in the tumor microenvironment Kuriyama et al.
Extracellular vesicles are classified into exosomes, microvesicles, and apoptotic bodies based on the size or biogenesis of the vesicles Kuriyama et al. Under hypoxic conditions, tumor cells release extracellular vesicles to a larger extent compared to cells in a normoxic environment Kuriyama et al.
Growing evidence points to the role of tumor-derived extracellular vesicles in tumor angiogenesis of breast cancer. recently reported that extracellular vesicles derived from breast cancer cells are highly enriched with miRNAp which enhanced proliferation and migration of endothelial cells in vitro and angiogenesis and metastasis of breast cancer in vivo Lu et al.
Microvesicles rich in a special VEGF isoform activated VEGFR and induced angiogenesis while being resistant to bevacizumab Feng et al. Exosome-mediated transfer of breast cancer-secreted miRNA efficiently destroyed tight junctions in endothelial monolayers associated with increased vascular permeability Zhou et al.
Few studies showed that extracellular vesicles can be targeted to prevent breast cancer metastasis and restore the activity of anti-angiogenic drugs Zhou et al.
Aslan et al. showed that docosahexaenoic acid decreased the expression of pro-angiogenic genes including HIF-1α, TGF-β, and VEGFR in breast cancer cells and their secreted exosomes Aslan et al. Also, docosahexaenoic acid altered miRNA content in breast cancer cells and their derived exosomes in favor of the inhibition of angiogenesis Aslan et al.
Taken together, miRNAs and extracellular vesicles can be selectively targeted to reduce vascularization in breast cancer providing a novel approach for angiogenesis inhibition Gallach et al.
Normal vasculature is needed for immunosurveillance and efficient detection and killing of cancer cells by immune cells. Disorganized tumor vessels create a selective immune cell barrier limiting the extravasation of immune cells, particularly the cytotoxic T lymphocytes into blood vessels and tumor tissue Yang et al.
Further, hypoxia in the tumor microenvironment promotes lactate accumulation, extracellular acidosis, VEGF overexpression, and VEGFR activation, all of which are known drivers of immune cell tolerance and immunosuppressive status Mendler et al.
Endothelial cells are the first to come into contact with immune cells while infiltrating from the circulation into the tumor tissue Solimando et al. Interestingly, tumor endothelial cells expressed PD-L1 and produced immunosuppressive activity contributing to tumor immune evasion in a mouse model of melanoma Taguchi et al.
Further, leukocyte adhesion was remarkably diminished in tumor vessels Dirkx et al. Tumors secrete angiogenic growth factors that can downregulate endothelial adhesion molecules essential for the interactions with granulocytes, macrophages, and natural killer cells on the vascular endothelium Griffioen, The suppression of these selective adhesion molecules leads to the loss of the adhesive properties of the tumor endothelium thereby impairing immune cell infiltration to tumor tissues.
Solimando et al. showed that junctional adhesion molecule-A JAM-A is an important factor influencing angiogenesis and extra-medullary dissemination in patients with multiple myeloma and its targeting suppressed multiple myeloma-associated angiogenesis both in vitro and in vivo Solimando et al.
Bednarek et al. recently demonstrated that targeting JAM-A with an antagonistic peptide inhibited the adhesion and trans-endothelial migration of breast cancer cells Bednarek et al.
In breast cancer, vascular cell adhesion molecule-1 was aberrantly expressed and mediated angiogenesis and metastasis by binding to its ligand α4β1integrin Sharma et al. Earlier findings also showed that angiogenic stimuli in the microenvironment of breast cancer may influence the expression of endothelial adhesion molecules to prevent leukocyte infiltration to tumor tissue Bouma-Ter Steege et al.
Therefore, selective targeting of adhesion molecules and normalizing tumor vasculature could improve immune cell endothelial adhesion and strengthen the antitumor immune response in epithelial tumors, including breast cancer. A growing body of evidence describes the interplay between immune cells and vasculature in the tumor microenvironment.
The immune response and vascular normalization seem to be mutually regulated Fukumura et al. Normalization of the tumor vasculature improves the infiltration of immune effector cells into tumors enhancing antitumor immune activity Fukumura et al.
Likewise, immunotherapy can promote vascular normalization which further improves the effectiveness of immunotherapeutic drugs and response to anti-angiogenic therapies Huang et al. In preclinical models of breast cancer, immune checkpoint inhibitors induced normalization of tumor vasculature and increased infiltration of immune cells into breast tumors Tian et al.
Together, the combination of anti-angiogenic and immunotherapeutic drugs might be an attractive approach to increase the effectiveness of each class of drugs and reduce the emergence of drug resistance Fukumura et al.
The combination treatment has shown encouraging results in various cancer types Ciciola et al. In a preclinical study, Allen et al. revealed that treatment with a combination of anti-VEGFR-2 and anti-PD-L1 antibodies sensitized tumors to anti-angiogenic therapy and prolonged its efficacy in breast cancer Allen et al.
Li et al. recently demonstrated a dose-dependent synergism for the combined treatment of anti-angiogenic therapy and immune checkpoint blockade Li et al. In this regard, the combination of low-dose anti-VEGFR2 antibody with anti-programmed cell death protein-1 PD-1 therapy normalized tumor vasculature, induced immune cell infiltration, and upregulated PD-1 expression on immune cells in syngeneic breast cancer mouse models.
Additionally, the combined treatment was effective and tolerable in patients with advanced TNBC Li et al. An open-label, randomized, parallel, phase II trial investigated the combination treatment of apatinib, a VEGFR-2 tyrosine kinase inhibitor with the anti-PD-1 monoclonal antibody camrelizumab in patients with advanced TNBC Liu et al.
The results showed that the combination treatment produced favorable therapeutic outcomes in terms of improved objective response rate and PFS which was associated with increased tumor-infiltrating lymphocytes.
The adverse events were manageable and included elevated aminotransferases and hand-foot syndrome Liu et al. Multiple clinical trials of combining anti-angiogenic therapy and immune checkpoint inhibitors are underway Zirlik and Duyster, The nanotechnology-based approach is an emerging strategy for the development of therapies targeting tumor angiogenesis which could improve the current pharmacokinetic profiles of anti-angiogenic drugs and favor their selective accumulation in tumors Banerjee et al.
Radical-containing nanoparticles produced in vitro and in vivo anti-angiogenic activity in a breast cancer model that was mediated by suppressing VEGF in cancer cells Shashni et al. Nanoparticles were also utilized to deliver a combination of therapy for breast cancer to produce anticancer and anti-angiogenic activity Zhao et al.
In a recent study by Gong et al. Table 3 provides a list of novel approaches for targeting vascular growth and angiogenesis in breast cancer. TABLE 3. Breast cancer is a notable example where anti-angiogenic agents had constantly failed to make a significant impact on the survival of patients in clinical settings.
One essential aspect to improve the efficacy of clinically available anti-angiogenic drugs is to better understand the vascular biology of breast cancer at the different stages and molecular types of the disease.
Besides, a greater understanding of the adaptive and intrinsic resistance mechanisms would enhance the proper utilization of angiogenesis inhibitors. Further evaluation for the role of stromal cells within the tumor microenvironment in mediating resistance to anti-angiogenic drugs will improve the efficacy and durability of anti-angiogenic therapy.
Another important facet to consider for the limited activity of angiogenesis inhibitors in breast cancer is the population under examination to allow the identification of breast cancer patients who would benefit most from anti-angiogenic drugs. Furthermore, there are several ongoing efforts to describe novel strategies to inhibit tumor angiogenesis through pericyte targeting, the use of immunotherapy, miRNAs, and the implementation of nanotechnology.
Despite the preclinical success of many of these strategies, limited clinical evidence is available to support their implementation in breast cancer treatment.
NMA conceived the manuscript. All authors listed wrote the manuscript and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Adair Th, M. Google Scholar.
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Other angiogenesis inhibitor drugs work on a different part of the process, by stopping VEGF receptors from sending signals to blood vessel cells. These drugs are known as tyrosine kinase inhibitors TKI. Sunitinib Sutent ® is an example of a tyrosine kinase inhibitor.
For this reason, these drugs are typically used in combination with chemotherapy or other treatments. Angiogenesis inhibitors are particularly effective for treating liver cancer , kidney cancer and neuroendocrine tumors.
Since they act on blood vessel formation and not the tumor itself, the side effects of angiogenesis inhibitors are different than traditional chemotherapy drugs.
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Jump To:. Angiogenesis Inhibitors. Possible side effects include: High blood pressure hypertension Wounds that are slow to heal Increased risk of internal bleeding Perforation of the intestine rare. We're here for you.
Thank you for visiting nature. You are using a browser Anti-angiogenesid with Anti-angiogenesis clinical trials Anti-angiogenesi for CSS. Anti-angiogenesis clinical trials Anti-aging skincare the best Anti-angiogwnesis, we recommend you use a more triials to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis.
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