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Ombrabulin(AVE8062)

Description of ombrabulin: ombrabulin is a synthetic water-soluble analogue of combretastatin A4, derived from the South African willow bush (Combretum caffrum), with potential vascular-disrupting and antineoplastic activities. Ombrabulin binds to the colchicine binding site of endothelial cell tubulin, inhibiting tubulin polymerization and inducing mitotic arrest and apoptosis in endothelial cells. As apoptotic endothelial cells detach from their substrata, tumor blood vessels collapse; the acute disruption of tumor blood flow may result in tumor necrosis. Ombrabulin was discovered by Ajinomoto and under development by Sanofi-Aventis. It is currently in Phase III clinical trials for the treatment of advanced-stage soft-tissue sarcoma. Ombrabulin was granted orphan drug status by the European Medicines Agency in April 2011. Ombrabulin is a combretastatin A-4 derivative that exerts its antitumor effect by disrupting the formation of blood vessels needed for tumor growth. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:  Sanofi-aventis  

Ombrabulin (AVE8084 or AC7700) is a novel water-soluble combretastatin A-4 derivative, can abruptly and irreversibly stopped tumour blood flow. As a result of this interrupted supply of nutrients, extensive necrosis was induced within the tumour.  Tumour blood flow stanching induced by AC7700 may become an effective therapeutic strategy for all cancers, including refractory cancers because the therapeutic effect is independent of tumour site and specific type of cancer.

Highlight on recent research using ombrabulin (AVE8084 or AC7700)

1. Antitumor and antivascular effects of AVE8062 in ovarian carcinoma.

According to research results published by Kim et al,   the in vitro and in vivo effects of AVE8062 alone and in combination with docetaxel were tested in chemotherapy-sensitive and chemotherapy-resistant ovarian cancer models. Tumors were analyzed for necrosis, microvessel density, endothelial cell apoptosis, and proliferation following treatment. The effect of AVE8062 on tumor regression and metabolic activity was examined by magnetic resonance (MR) or by [18F]fluorodeoxyglucose ([18F]FDG) uptake by positron emission tomography (PET) with MR imaging, respectively. AVE8062 monotherapy was effective in inhibiting tumor growth in all models (range 43-51% versus control; P < 0.05). Combination therapy was even more effective in inhibiting tumor growth (range 76-90% compared with controls, P < 0.01). AVE8062 in combination with chemotherapy significantly prolonged survival in HeyA8-injected mice (P < 0.001) compared with other groups. AVE8062-based therapy resulted in rapid development of central tumor necrosis, decreased microvessel density, decreased proliferation, and induction of apoptosis of tumor-associated endothelial cells. MR imaging showed regression of established HeyA8 ovarian tumors and [18F]FDG PET with MR showed rapid decrease in metabolic activity after AVE8062 therapy. Combination of AVE8062 plus docetaxel results in potent inhibition of ovarian cancer growth. These results suggest that AVE8062 may be useful as a clinical therapeutic approach for ovarian cancer patients and that functional [18F]FDG PET imaging may predict clinical response before an anatomic reduction in tumor size. [source: Kim TJ, Ravoori M, Landen CN, Kamat AA, Han LY, Lu C, Lin YG, Merritt WM, Jennings N, Spannuth WA, Langley R, Gershenson DM, Coleman RL, Kundra V, Sood AK. Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. Antitumor and antivascular effects of AVE8062 in ovarian carcinoma. Cancer Res. 2007 Oct 1;67(19):9337-45.  http://www.ncbi.nlm.nih.gov/pubmed/17909042].

2. AVE8062: a new combretastatin derivative vascular disrupting agent.

Angiogenesis has an essential role in promoting and supporting tumor growth and it is an important therapeutic target. The tumor vascular network is the result of pro-angiogenic and inhibitory factors as well as of the interaction between endothelial cells and extracellular matrix. Different antiangiogenic therapeutics have been developed to improve tumor control through vascular-targeting agents (VTA). VTAs can be divided into two groups: antiangiogenic agents and vascular-disrupting agents (VDAs). VTAs inhibit specific factors required to induce and direct the angiogenic process, with major activity against small tumor masses and at the tumor periphery, encompassing monoclonal antibodies and small molecules inhibitors of the tyrosine kinase domain of the VEGF receptor. VDAs specifically target and destroy well-established tumor vessels with ischemia and destruction of large masses with central hemorrhagic necrosis and survival of a thin peripheral tumor layer. VDAs can be divided into biologics, such as ligand-based, and small-molecule agents; this second group includes small-molecule VDAs like flavonoids, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and microtubule-destabilizing agents. In this review we will discuss the mechanism of action, as well as the preclinical and clinical results, of one of the most promising antitubulin agents: the combretastatin A4-phosphate derivative, AVE8062A. [source: Delmonte A, Sessa C. Oncology Institute of Southern Switzerland, Ospedale S Giovanni, Bellinzona, Switzerland. AVE8062: a new combretastatin derivative vascular disrupting agent. Expert Opin Investig Drugs. 2009 Oct;18(10):1541-8.]

3. Early quantitative evaluation of a tumor vasculature disruptive agent AVE8062 using dynamic contrast-enhanced ultrasonography.

OBJECTIVES: To evaluate the early tumor vasculature disrupting effects of the AVE8062 molecule and the feasibility of dynamic contrast-enhanced ultrasonography (DCE-US) in the quantitative assessment of these effects. MATERIAL AND METHODS: AVE8062 was administered at a single dose (41 mg/kg) to 40 melanoma-bearing nude mice, which were all imaged before and after drug administration (5 + 15 minutes, 1, 6, and 24 hours). Using an ultrasound scanner (Aplio, Toshiba), intratumor vessels were counted in power Doppler mode and tumor microvasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software for contrast-uptake quantification (Sonovue, Bracco). The peak intensity (PI), time-to-PI (T PI), and full-width at half maximum (FWHM) were extracted from the time-intensity curves expressed as linear raw data. Histologic analysis evaluated microvessel density (MVD) and necrosis at each time point studied. Statistical significance was estimated (paired sum rank and Mann-Whitney tests) to evaluate drug activity and to compare its efficacy at the different time points. RESULTS: In power Doppler mode, intratumoral vessels depletion started 15 minutes postinjection (32%, P = 0.004) and the decrease was maximal at 6 hours (51%, P = 0.002). PI decreased by 3.5- and 45.7-fold at 1 and 6 hours, respectively, compared with preinjection values (P = 0.016 and P = 0.008). The decrease at 6 hours was significantly different from the variation at 1 hour (P = 0.0012) and at 24 hours (P = 0.0008). T PI and FWHM showed a significant increase exclusively at 6 hours (P = 0.0034, P = 0.0039). Histology revealed significantly decreased MVD and increased necrosis at 24 hours (P < 0.01). CONCLUSION: DCE-US allowed quantitative in vivo evaluation of the functional effects of AVE8062, which was found most effective on tumoral microvasculature 6 hours after its administration. A clinical phase-1 study of AVE8062 is ongoing using the same ultrasonography methodology before and 6 and 24 hours postadministration. [source: Lavisse S, Lejeune P, Rouffiac V, Elie N, Bribes E, Demers B, Vrignaud P, Bissery MC, Brulé A, Koscielny S, Péronneau P, Lassau N. UPRES EA 4040, Univ Paris-Sud, Institut Gustave Roussy, Villejuif, France. Early quantitative evaluation of a tumor vasculature disruptive agent AVE8062 using dynamic contrast-enhanced ultrasonography.Invest Radiol. 2008 Feb;43(2):100-11.]

 1: Delmonte A, Sessa C. AVE8062: a new combretastatin derivative vascular disrupting agent. Expert Opin Investig Drugs. 2009 Oct;18(10):1541-8. Review. PubMed PMID: 19758109.

2: Hori K, Furumoto S, Kubota K. Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowth. Cancer Sci. 2008 Jul;99(7):1485-91. Epub 2008 Apr 29. PubMed PMID: 18452559.

3: Cai SX. Small molecule vascular disrupting agents: potential new drugs for cancer treatment. Recent Pat Anticancer Drug Discov. 2007 Jan;2(1):79-101. Review. PubMed PMID: 18221055.

4: Lavisse S, Lejeune P, Rouffiac V, Elie N, Bribes E, Demers B, Vrignaud P, Bissery MC, Brulé A, Koscielny S, Péronneau P, Lassau N. Early quantitative evaluation of a tumor vasculature disruptive agent AVE8062 using dynamic contrast-enhanced ultrasonography. Invest Radiol. 2008 Feb;43(2):100-11. PubMed PMID: 18197062.

5: Kim TJ, Ravoori M, Landen CN, Kamat AA, Han LY, Lu C, Lin YG, Merritt WM, Jennings N, Spannuth WA, Langley R, Gershenson DM, Coleman RL, Kundra V, Sood AK. Antitumor and antivascular effects of AVE8062 in ovarian carcinoma. Cancer Res. 2007 Oct 1;67(19):9337-45. PubMed PMID: 17909042.

6: Lippert JW 3rd. Vascular disrupting agents. Bioorg Med Chem. 2007 Jan 15;15(2):605-15. Epub 2006 Oct 27. PubMed PMID: 17070061.

7: Hori K. Antineoplastic strategy: irreversible tumor blood flow stasis induced by the combretastatin A-4 derivative AVE8062 (AC7700). Chemotherapy. 2005 Oct;51(6):357-60. Epub 2005 Oct 14. Review. PubMed PMID: 16227690.

8: Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004 Jan 15;10(2):415-27. Review. PubMed PMID: 14760060.

9: Hori K, Saito S. Induction of tumour blood flow stasis and necrosis: a new function for epinephrine similar to that of combretastatin A-4 derivative AVE8062 (AC7700). Br J Cancer. 2004 Jan 26;90(2):549-53. PubMed PMID: 14735207; PubMed Central PMCID: PMC2409553.

10: Hori K, Saito S. Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis. Br J Cancer. 2003 Oct 6;89(7):1334-44. PubMed PMID: 14520469; PubMed Central PMCID: PMC2394288.

11: Hori K, Saito S, Sato Y, Akita H, Kawaguchi T, Sugiyama K, Sato H. Differential relationship between changes in tumour size and microcirculatory functions induced by therapy with an antivascular drug and with cytotoxic drugs. implications for the evaluation of therapeutic efficacy of AC7700 (AVE8062). Eur J Cancer. 2003 Sep;39(13):1957-66. PubMed PMID: 12932676.

12: Morinaga Y, Suga Y, Ehara S, Harada K, Nihei Y, Suzuki M. Combination effect of AC-7700, a novel combretastatin A-4 derivative, and cisplatin against murine and human tumors in vivo. Cancer Sci. 2003 Feb;94(2):200-4. PubMed PMID: 12708497.

13: Ohno T, Kawano K, Sasaki A, Aramaki M, Tahara K, Etoh T, Kitano S. Antitumor and antivascular effects of AC-7700, a combretastatin A-4 derivative, against rat liver cancer. Int J Clin Oncol. 2002 Jun;7(3):171-6. PubMed PMID: 12109519.

14: Hori K, Saito S, Kubota K. A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs. Br J Cancer. 2002 May 20;86(10):1604-14. PubMed PMID: 12085211; PubMed Central PMCID: PMC2746587.

15: Tozer GM, Kanthou C, Parkins CS, Hill SA. The biology of the combretastatins as tumour vascular targeting agents. Int J Exp Pathol. 2002 Feb;83(1):21-38. Review. PubMed PMID: 12059907.

16: Hori K, Saito S, Sato Y, Kubota K. Stoppage of blood flow in 3-methylcholanthrene-induced autochthonous primary tumor due to a novel combretastatin A-4 derivative, AC7700, and its antitumor effect. Med Sci Monit. 2001 Jan-Feb;7(1):26-33. PubMed PMID: 11208488.

17: von Angerer E. Tubulin as a target for anticancer drugs. Curr Opin Drug Discov Devel. 2000 Sep;3(5):575-84. PubMed PMID: 19649885.

18: Ohsumi K, Hatanaka T, Nakagawa R, Fukuda Y, Morinaga Y, Suga Y, Nihei Y, Ohishi K, Akiyama Y, Tsuji T. Synthesis and antitumor activities of amino acid prodrugs of amino-combretastatins. Anticancer Drug Des. 1999 Dec;14(6):539-48. PubMed PMID: 10834274.

19: Nihei Y, Suzuki M, Okano A, Tsuji T, Akiyama Y, Tsuruo T, Saito S, Hori K, Sato Y. Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumor therapy. Jpn J Cancer Res. 1999 Dec;90(12):1387-95. PubMed PMID: 10665658.

20: Hori K, Saito S, Nihei Y, Suzuki M, Sato Y. Antitumor effects due to irreversible stoppage of tumor tissue blood flow: evaluation of a novel combretastatin A-4 derivative, AC7700. Jpn J Cancer Res. 1999 Sep;90(9):1026-38. PubMed PMID: 10551334.

21: Nihei Y, Suga Y, Morinaga Y, Ohishi K, Okano A, Ohsumi K, Hatanaka T, Nakagawa R, Tsuji T, Akiyama Y, Saito S, Hori K, Sato Y, Tsuruo T. A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors. Jpn J Cancer Res. 1999 Sep;90(9):1016-25. PubMed PMID: 10551333.