VEGF INHIBITORS FOR CANCER THERAPY
Abstract
Despite significant advances in systemic therapies, radiation oncology, and surgical techniques, many patients with cancer are still incurable. A novel therapeutic approach has been to target the vascular endothelial growth factors (VEGFs) which are often mutated and/or over-expressed in many tumors. The ligands and receptors of VEGF family are well established as key regulators of angiogenesis and vasculogenesis processes. VEGF is a homodimeric, basic, 45 kDa glycoprotein specific for vascular endothelial cells. Specifically, VEGF participates in regulation of the female reproductive cycle, wound healing, inflammation, vascular permeability, vascular tone, hematopoiesis and also contributes to pathological angiogenesis disorders such as cancer, rheumatoid arthritis, diabetic retinopathy and the neovascular form of macular degeneration. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Clinical trials have anti-VEGF therapies are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. The aim of present review is on the cellular responses of VEGF inhibitors and their implications for cancer therapy.
Keywords:
Vascular Endothelial Growth Factor, Tyrosine Kinase, Kinase InhibitorsDOI
https://doi.org/10.25004/IJPSDR.2010.020101References
Roy H, Bhardwaj S, Yla-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006; 580: 2879-2887.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004; 25: 581-611.
Weis SM, Cheresh DA. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005; 437: 497-504.
Cui TG, Foster RR, Saleem M. Differentiated human podocytes endogenously express an inhibitory isoform of vascular endothelial growth factor (VEGF165b) mRNA and protein. Am J Physiol Renal Physiol. 2004; 286: F767-F773.
Ortega N, Hutchings H, Plouet J. Signal relays in the VEGF system. Front Biosci. 1999; 4: 141-152.
De VC, Escobedo JA, Ueno H. The Fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255: 989-991.
Afuwape AO, Kiriakidis S, Paleolog EM. The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis. Histol. Histopathol. 2003; 17(3): 961-972.
Holmes DI, Zachary I. The vascular endothelial growth factor (VEGF) family: Angiogenic factors in health and disease. Genome Biol. 2005; 6(2): 209.
Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 2001; 280(6): C1358-C1366.
Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina 2005; 25(2): 111-118.
Ria R, Roccaro AM, Merchionne F. Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003; 17(10): 1961–1966.
Terman B, Khandke L, Dougher-Vermazan M. VEGF receptor subtypes KDR and FLT1 show different sensitivities to heparin and placenta growth factor. Growth Factors 1994; 11: 187-195.
Chen X, Veeravagu A, Hsu A, Cai W, Hou L, Tse V. Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor Inhibitors as Anti-Angiogenic Agents in Cancer Therapy. Recent Patents on Anti-Cancer Drug Discovery 2007; 2: 59-71.
Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 2008; 8(8): 592–603.
Achen MG, Jeltsch M, Kukk E. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci. 1998; 95: 548-553.
Partanen TA, Arola J, Saaristo A. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J. 2000; 14: 2087-2096.
Achen MG, Mann GB, Stacker SA. Targeting Lymphangiogenesis to prevent tumour metastasis. Br J Cancer 2006; 94: 1355-1360.
Patan S. Vasculogenesis and angiogenesis. Cancer Treat. Res. 2004; 117: 3–32.
Shalaby F, Rossant J, Yamaguchi TP. Failure of blood island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376: 62-66.
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380: 435–439.
Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439–442.
Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, Hong K, Marsters JC, Ferrara N, VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002; 417: 954–958.
Shida A, Fujioka S, Ishibashi Y, Kobayashi K, Nimura H, Mitsumori N, Suzuki Y, Kawakami M, Urashima M, Prognostic significance of vascular endothelial growth factor D in gastric carcinoma. World J Surg. 2005; 29(12): 1600-1607.
Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE. 2001; 112: RE21.
Tallquist M, Soriano P, Klinghoffer R. Growth factor signaling pathways in vascular development. Oncogene 1999; 18: 7917-7932.
Chae JK, Kim I, Lim ST, Chung MJ, Kim WH, Kim HG, Ko JK, Koh GY. Co-administration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler Thromb Vasc Biol. 2000; 20(12): 2573-2578.
Rusnati M, Urbinati C, Musulin B, Ribatti D, Albini A, Noonan D, Marchisone C, Waltenberger J, Presta M, Activation of endothelial cell mitogen activated protein kinase ERK(1/2) by extracellular HIV-1 Tat protein. Endothelium. 2001; 8(1): 65-74.
Ganju RK, Munshi N, Nair BC, Liu ZY, Gill P, Groopman JE. Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. J Virol. 1998; 72(7): 6131-6137.
Koistinen P, Siitonen T, Mantymaa P, Saily M, Kinnula V, Savolainen ER, Soini Y. Regulation of the acute myeloid leukemia cell line OCI/AML-2 by endothelial nitric oxide synthase under the control of a vascular endothelial growth factor signaling system. Leukemia. 2001; 15(9): 1433-1441.
Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3: 401–410.
Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg. 1972; 175: 409–419.
Clarke S, Sharma R. Angiogenesis inhibitors in cancer – mechanisms of action. Aust Prescr. 2006; 29: 9–12.
Sauder DN, DeKoven J, Champagne P, Croteau D, Dupont E.N. , (AE-941), an inhibitor of angiogenesis: randomized phase I/II clinical trial results in patients with plaque psoriasis. J Am Acad Dermatol. 2002; 47: 535–541.
Mazitschek R, Giannis A. Inhibitors of angiogenesis and cancer-related receptor tyrosine kinases. Current Opinion in Chemical Biology 2004; 8: 432–441.
Willett CG, Boucher Y, di Tomaso E. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004; 10: 145–147.
Rini BI. Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res. 2007; 13(4): 1098–1106.
Mayer RJ. Two Steps Forward in the Treatment of Colorectal Cancer. N Engl J Med. 2004; 350: 2406-2408.
Azad R, Chandra P. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Indian journal of ophthalmology 2007; 55(4): 319.
Velcheti V, Viswanathan A, Govindan R. The Proportion of Patients with Metastatic Non-small Cell Lung Cancer Potentially Eligible for Treatment with Bevacizumab: A Single Institutional Survey. Journal of Thoracic Oncology 2006; 1(5): 501.
Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006; 13(16): 1845-1857.
Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000; 60: 2178-2189.
Jost LM, Gschwind HP, Jalava T. Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients. Drug Metabolism and Disposition 2006; 34(11): 1817–1828.
Los M, Roodhart JM, Voest EE. Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. The Oncologist 2007; 12(4): 443–450.
Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL. Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours. Expert Opin Investig Drugs 2007; 16(3): 367–379.
Mariani SM. Antiangiogenesis cocktails—stirred or shaken. Medscape General Medicine 2004; 6(4): 21.
Roboz GJ, Giles FJ, List AF. Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia. 2006; 20: 952-957.
Kuenen BC, Tabernero J, Baselga J. Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma. Clin Cancer Res. 2003; 9:1648–1655.
Lockhart A, Cropp G, Berlin J, Donnelly E, Schumaker R, Schaaf L, Hande K, Fleischer A, Hannah A, Rothenberg M. Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer. Am J Clin Oncol. 2006; 29(2): 109–115.
Hoff PM, Wolff RA, Bogaard K. A Phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma. Jpn J Clin Oncol. 2006; 36:100-103.
Hunt S. Technology evaluation: IMC-1C11, ImClone Systems. Curr Opin Mol Ther. 2001; 3(4):418-424.
Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004; 351(27): 2805-2816.
Hartmann JT, Kanz L. Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol. 2008; 144(11): 1525–1526.
Eisen T, Ahmad M, Gore E. Phase I trial of BAY 43-9006 (sorafenib) combined with dacarbazine (DTIC) in metastatic melanoma patients. Proc Annu Meet Am Soc Clin Oncol. 2005; 23:7508.
Siu LL, Awada A, Takimoto CH. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res. 2006; 12: 144-151.
Kim ES, Serur A, Huang J, Manley CA, McCrudden KW, Frischer JS, Soffer SZ, Ring L, Yamashiro, DJ. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci. 2002; 99: 11399–11404.
Kadenhe-Chiweshe A, Papa J, McCrudden K, Feirt N, Rudge J, Holash J, Yancopoulos G, Kandel J, Yamashiro D. Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation. Mol Cancer Res. 2008; 6(1): 1-9.
Holash J, Davis S, Papadopoulos N, Croll S, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Yancopoulos G, Zudge J. VEGF-Trap: A VEGF blocker with potent antitumor effects. PNAS 2002; 99(17): 11393-11398.
Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 2000; 60: 6253–6258.
Gomez-Manzano C, Holash J, Fueyo J, Xu J, Conrad C, Aldape K, Groot J, Bekele J, Yung W. VEGF Trap induces antiglioma effect at different stages of disease. Neuro Oncol. 2008; 10(6): 940-945.
Dupont J, Rothenberg ML, Spriggs DR. Safety and pharmacokinetics of intravenous VEGF Trap in a phase I clinical trial of patients with advanced solid tumors. Proc Annu Meet Am Soc Clin Oncol. 2005; 23: 3029.
George D. Phase 2 Studies of Sunitinib and AG013736 in Patients with Cytokine-Refractory Renal Cell Carcinoma. Clin Cancer Res. 2007; 13: 753.
Giles FJ, Bellamy WT, Estrov Z. The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk Res. 2006; 30: 801-811.
Rugo HS, Herbst RS, Liu G. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005; 23: 5474-5483.
Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Partridge SC, Shane TM, Lu Y, Brasch RC, Hylton NM. AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 2007; 25(3): 319-327.
Kobayashi H, Gail E, Lockridge J, Rothenberg M, Sandier A, Bryant C, Cooper W, Holden S, Aitchison R. Safety and pharmacokinetic study of RPI.4610 (ANGIOZYME), an anti-VEGFR-1 ribozyme, in combination with carboplatin and paclitaxel in patients with advanced solid tumors. Cancer chemotherapy and pharmacology 2005; 56(4): 329-336.
Ideyama Y, Yamano M, Kuromitsu S, Tajinda K, Samizu K, Hisamichi H, Matsuhisa A, Shirasuna K, Kudoh M, Shibasaki M. YM-359445, an orally bioavailable vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, has highly potent antitumor activity against established tumors. Clin Cancer Res. 2006; 12(5): 1630-1638.
Amino N, Ideyama Y, Yamano M. YM-359445, an orally bioavailable vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, has highly potent antitumor activity against established tumors. Clin Cancer Res. 2006; 12: 1630-1638.
Fabbro D, Manley PW. Su-6668.SUGEN. Curr Opin Investig Drugs 2001; 2: 1142–1148.
Brahmer JR, Kelsey S, Scigalla P. A phase I study of SU6668 in patients with refractory solid tumors. Proc Annu Meet Am Soc Clin Oncol. 2002; 21: 335.
Morabito A, Piccirillo MC, Falasconi F, Feo GD, Giudice AD, Bryce J, Maio MD, Maio ED, Normanno N, Perrone F. Vandetanib (ZD6474), a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinases: Current Status and Future Directions. The Oncologist 2009; 14(4): 378-390.
Fung A, Lalwani G, Rosenfeld P, Dubovy S, Michels S, Feuer W, Puliafito C, Davis J, Flynn JR, Esquiabro M. An Optical Coherence Tomography-Guided, Variable Dosing Regimen with Intravitreal Ranibizumab (Lucentis) for Neovascular Age-related Macular Degeneration. American Journal of Ophthalmology 2007; 143(4): 566-583.
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