Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 1/2013

01-01-2013 | Review Article

Assessing the in vivo efficacy of biologic antiangiogenic therapies

Authors: Peter M. Wilson, Melissa J. LaBonte, Heinz-Josef Lenz

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2013

Login to get access

Abstract

Purpose

To review key clinical issues underlying the assessment of in vivo efficacy when using antiangiogenic therapies for cancer treatment.

Methods

Literature relevant to use of antiangiogenic therapies in cancer was reviewed, with particular emphasis on the assessment of in vivo efficacy of these agents, as well as additional angiogenic factors that could play a role in escape from angiogenesis inhibition.

Results

In order to grow and metastasize, tumors need to continually acquire new blood supplies; therefore, therapeutic inhibition of angiogenesis has become a component of anticancer treatment for many tumor types. Bevacizumab, a humanized monoclonal antibody directed at vascular endothelial growth factor A (VEGF-A), has shown activity in combination with chemotherapy in metastatic colorectal cancer. Nevertheless, the use of antiangiogenic therapies remains suboptimal; specifically, optimal dose, duration of therapy, and combination of agents remain unknown. Also, at present, it is not possible to determine which patients are most likely to respond to a given form of antiangiogenic therapy. There has been increased recognition of alternative pathways possibly associated with disease progression in patients undergoing antiangiogenic therapy targeted at VEGF-A. Multiligand-targeted antiangiogenic therapies, such as ziv-aflibercept (formerly known as aflibercept, VEGF Trap), are currently undergoing clinical evaluation. Ziv-aflibercept forms monomeric complexes with VEGF-A, VEGF-B, and PlGF, which have a long half-life, allowing optimization of ziv-aflibercept doses and angiogenic blockage.

Conclusions

Although antiangiogenic therapies have increased treatment options for cancer patients, their use is limited by a lack of established and standardized methodology to evaluate their efficacy in vivo. Circulating endothelial cells, hypertension, and several molecular and imaging-based markers have potential for use as biomarkers in these patients and may better define appropriate patient populations.
Literature
1.
Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8:942–956PubMedCrossRef
2.
3.
Folkman J, Merler E, Abernathy C, Williams G (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275–288PubMedCrossRef
4.
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307PubMedCrossRef
5.
Liu Y, Han ZP, Zhang SS, Jing YY, Bu XX, Wang CY, Sun K, Jiang GC, Zhao X, Li R, Gao L, Zhao QD, Wu MC, Wei LX (2011) Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer. J Biol Chem 286:25007–25015PubMedCrossRef
6.
Gerber HP, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 6:671–680
7.
Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62PubMedCrossRef
8.
9.
Ferrara N (2004) Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 9(Suppl 1):2–10PubMedCrossRef
10.
11.
Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRef
12.
Gerger A, LaBonte M, Lenz HJ (2011) Molecular predictors of response to antiangiogenesis therapies. Cancer J 17:134–141PubMedCrossRef
13.
Murukesh N, Dive C, Jayson GC (2010) Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer 5:8–18CrossRef
14.
Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, Lieu C, Yan S, Tran HT, Ellis LM, Abbruzzese JL, Heymach JV (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453–459PubMedCrossRef
15.
Loupakis F, Cremolini C, Fioravanti A et al (2011) Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer 104:1262–1269PubMedCrossRef
16.
Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463-475
17.
Park JW, Kerbel RS, Kelloff GJ, Barrett JC, Chabner BA, Parkinson DR, Peck J, Ruddon RW, Sigman CC, Slamon DJ (2004) Rationale for biomarkers and surrogate en points in mechanism-driven oncology drug development. Clin Cancer Res 10:3885–3896PubMedCrossRef
18.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRef
19.
Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335PubMedCrossRef
20.
Avastin [prescribing information] (2011) Roche, South San Francisco, CA
21.
22.
Chu QS (2009) Ziv-aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors. Expert Opin Biol Ther 9:263–271PubMedCrossRef
23.
Sweeney CJ, Miller KD, Sledge GW Jr (2003) Resistance in the anti-angiogenic era: nay-saying or a word of caution? Trends Mol Med 9:24–29PubMedCrossRef
24.
Martinez-Poveda B, Gomez V, Alcaide-German M, Perruca S, Vazquez S, Alba LE, Casanovas O, Garcia-Bermejo ML, Peso L, Jimenez B (2011) Non-invasive monitoring of hypoxia-inducible factor activation by optical imaging during antiangiogenic treatment in a xenograft model of ovarian carcinoma. Int J Oncol 39:543–552PubMed
25.
Rudge JS, Holash J, Hylton D, Russell M, Jiang S, Leidich R, Papadopoulos N, Pyles EA, Torri A, Wiegand SJ, Thurston G, Stahl N, Yancopoulos GD (2007) VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci USA 104:18363–18370PubMedCrossRef
26.
Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611PubMedCrossRef
27.
Bates RC, Goldsmith JD, Bachelder RE, Brown C, Shibuya M, Oettgen P, Mercurio AM (2003) Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. Curr Biol 13:1721–1727PubMedCrossRef
28.
Boscolo E, Mulliken JB, Bischoff J (2011) VEGFR-1 mediates endothelial differentiation and formation of blood vessels in a murine model of infantile hemangioma. Am J Pathol 179:2266–2277PubMedCrossRef
29.
Hilmi C, Guyot M, Pagès G (2012) VEGF spliced variants: possible role of anti-angiogenesis therapy. J Nucleic Acids 2012:162692PubMed
30.
Nowak DG, Amin EM, Rennel ES, Hoareau-Aveilla C, Gammons M, Damodoran G, Hagiwara M, Harper SJ, Woolard J, Ladomery MR, Bates DO (2010) Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem 285:5532–5540PubMedCrossRef
31.
Peiris-Pagès M, Harper SJ, Bates DO, Ramani P (2010) Balance of pro- versus anti-angiogenic splice isoforms of vascular endothelial growth factor as a regulator of neuroblastoma growth. J Pathol 222:138–147PubMedCrossRef
32.
Rennel ES, Varey AH, Churchill AJ, Wheatley ER, Stewart L, Mather S, Bates DO, Harper SJ (2009) VEGF(121)b, a new member of the VEGF(xxx)b family of VEGF-A splice isoforms, inhibits neovascularisation and tumour growth in vivo. Br J Cancer 101:1183–1193PubMedCrossRef
33.
Pritchard-Jones RO, Dunn DB, Qiu Y, Varey AH, Orlando A, Rigby H, Harper SJ, Bates DO (2007) Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 97:223–230
34.
Paule B, Bastien L, Deslandes E, Cussenot O, Podgorniak MP, Allory Y, Naïmi B, Porcher R, de La Taille A, Menashi S, Calvo F, Mourah S (2010) Soluble isoforms of vascular endothelial growth factor are predictors of response to sunitinib in metastatic renal cell carcinomas. PLoS One 5:e10715PubMedCrossRef
35.
Li X, Lee C, Tang Z, Zhang F, Arjunan P, Li Y, Hou X, Kumar A, Dong L (2009) VEGF-B: a survival, or an angiogenic factor? Cell Adh Migr 3:322–327PubMedCrossRef
36.
Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581PubMedCrossRef
37.
Olofsson B, Pajusola K, von Euler G, Chilov D, Alitalo K, Eriksson U (1996) Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J Biol Chem 271:19310–19317PubMedCrossRef
38.
Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitalo K, Eriksson U (1998) Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci USA 95:11709–11714PubMedCrossRef
39.
Zhang F, Tang Z, Hou X, Lennartsson J, Li Y, Koch AW, Scotney P, Lee C, Arjunan P, Dong L, Kumar A, Rissanen TT, Wang B, Nagai N, Fons P, Fariss R, Zhang Y, Wawrousek E, Tansey G, Raber J, Fong GH, Ding H, Greenberg DA, Becker KG, Herbert JM, Nash A, Yla-Herttuala S, Cao Y, Watts RJ, Li X (2009) VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci USA 106:6152–6157PubMedCrossRef
40.
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583PubMedCrossRef
41.
Ribatti D (2008) The discovery of the placental growth factor and its role in angiogenesis: a historical review. Angiogenesis 11:215–221PubMedCrossRef
42.
Escudero-Esparza A, Martin TA, Davies ML, Jiang WG (2009) PGF isoforms, PlGF-1 and PlGF-2, in colorectal cancer and the prognostic significance. Cancer Genomics Proteomics 6:239–246PubMed
43.
Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61:1207–1213
44.
Bais C, Wu X, Yao J, Yang S, Crawford Y, McCutcheon K, Tan C, Kolumam G, Vernes JM, Eastham-Anderson J, Haughney P, Kowanetz M, Hagenbeek T, Kasman I, Reslan HB, Ross J, Van Bruggen N, Carano RA, Meng YJ, Hongo JA, Stephan JP, Shibuya M, Ferrara N (2010) PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141:166–177PubMedCrossRef
45.
Loges S, Schmidt T, Carmeliet P (2009) “Antimyeloangiogenic” therapy for cancer by inhibiting PlGF. Clin Cancer Res 15:3648–3653PubMedCrossRef
46.
Tew WP, Gordon M, Murren J, Dupont J, Pezzulli S, Aghajanian C, Sabbatini P, Mendelson D, Schwartz L, Gettinger S, Psyrri A, Cedarbaum JM, Spriggs DR (2010) Phase 1 study of ziv-aflibercept administered subcutaneously to patients with advanced solid tumors. Clin Cancer Res 16:358–366PubMedCrossRef
47.
Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 99:11393–11398
48.
Van Cutsem E, Tabernero J, Lakomy R, Prausova J, Ruff P, Van Hazel G, Moiseyenko V, Ferry D, McKendrick J, Tellier A, Castan R, Allegra C (2011) Intravenous (IV) ziv-aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for second line treatment of metastatic colorectal cancer (mCRC): results of a multinational Phase III trial (EFC10262-VELOUR). Abstract O-0024
49.
Sanofi-Aventis. Ziv-aflibercept versus placebo in combination with irinotecan and 5-FU in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin based regimen (VELOUR). In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda 2000- [Jan 1 2012]. Available from: http://​clinicaltrials.​gov/​ct2/​show/​NCT00561470 NLM Identifier:NCT00561470
50.
51.
52.
53.
Meyer T, Robles-Carrillo L, Desai H, Hatfield M, Amaya M, Francis J, Amirkhosravi A (2010) Comparison of platelet activating potential of bevacizumab + VEGF and ziv-aflibercept + VEGF complexes. 53rd annual meeting of the American Society of Hematology, December 10–13, 2011, San Diego, CA, Abstract 3600
54.
Norden-Zfoni A, Desai J, Manola J, Beaudry P, Force J, Maki R, Folkman J, Bello C, Baum C, DePrimo SE, Shalinsky DR, Demetri GD, Heymach JV (2007) Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res 13:2643–2650PubMedCrossRef
55.
Scartozzi M, Galizia E, Chiorrini S, Giampieri R, Berardi R, Pierantoni C, Cascinu S (2009) Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 20:227–230PubMedCrossRef
56.
Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24PubMedCrossRef
57.
Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104:17069–17074PubMedCrossRef
58.
Hirashima Y, Yamada Y, Tateishi U, Kato K, Miyake M, Horita Y, Akiyoshi K, Takashima A, Okita N, Takahari D, Nakajima T, Hamaguchi T, Shimada Y, Shirao K (2012) Pharmacokinetic parameters from 3-Tesla DCE-MRI as surrogate biomarkers of antitumor effects of bevacizumab plus FOLFIRI in colorectal cancer with liver metastasis. Int J Cancer 130:2359–2365
59.
Vriens D, de Geus-Oei LF, Heerschap A, van Laarhoven HW, Oyen WJ (2011) Vascular and metabolic response to bevacizumab-containing regimens in two patients with colorectal liver metastases measured by dynamic contrast-enhanced MRI and dynamic 18F-FDG-PET. Clin Colorectal Cancer 10:E1–E5PubMedCrossRef
60.
Bhojani MS, Nyati MK, Zhao L, Normolle DP, Ross BD, Lawrence TS, Rehemtulla A (2011) Molecular imaging of akt enables early prediction of response to molecular targeted therapy. Transl Oncol 4:122–125PubMed
61.
Beloueche-Babari M, Workman P, Leach MO (2011) Exploiting tumor metabolism for non-invasive imaging of the therapeutic activity of molecularly targeted anticancer agents. Cell Cycle 10:2883–2893PubMedCrossRef
Metadata
Title
Assessing the in vivo efficacy of biologic antiangiogenic therapies
Authors
Peter M. Wilson
Melissa J. LaBonte
Heinz-Josef Lenz
Publication date
01-01-2013
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-012-1978-8

Other articles of this Issue 1/2013

Cancer Chemotherapy and Pharmacology 1/2013 Go to the issue

Review Article

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Original Article

Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis

Original Article

Combination of low-dose docetaxel and standard-dose S-1 for the treatment of advanced gastric cancer: efficacy, toxicity, and potential predictive factor

Original Article

Erlotinib in patients with advanced lung squamous cell carcinoma

Original Article

Vinorelbine and capecitabine in anthracycline- and/or taxane-pretreated metastatic breast cancer: sequential or combinational?

Original Article

Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits