Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer

Cancer Research

Volumn 75, Issue 19, 2015, Pages 4086-4096

  Kuhnert, Frank ^a   Chen, Guoying ^a   Coetzee, Sandra ^a   Thambi, Nithya ^a   Hickey, Carlos ^a   Shan, Jing ^a   Kovalenko, Pavel ^a   Noguera Troise, Irene ^a,b   Smith, Eric ^a   Fairhurst, Jeanette ^a   Andreev, Julian ^a   Kirshner, Jessica R ^a   Papadopoulos, Nicholas ^a   Thurston, Gavin ^a  

^a REGENERON PHARMACEUTICALS INC   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DELTA LIKE 4 PROTEIN; ENOTICUMAB; NOTCH RECEPTOR; TUMOR PROTEIN; UNCLASSIFIED DRUG; VASCULOTROPIN; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; DLL4 PROTEIN, HUMAN; DLL4 PROTEIN, MOUSE; MEMBRANE PROTEIN; MONOCLONAL ANTIBODY; REGN421; SIGNAL PEPTIDE; VASCULAR ENDOTHELIAL GROWTH FACTOR A, MOUSE; VASCULOTROPIN A;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BINDING AFFINITY; BINDING SITE; CANCER INHIBITION; CONTROLLED STUDY; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG HALF LIFE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESPONSE; DRUG TARGETING; FEMALE; MOUSE; NONHUMAN; OVARY CANCER; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; SIGNAL TRANSDUCTION; STROMA CELL; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; DRUG SCREENING; ENDOTHELIUM CELL; GENETICS; HUMAN; IMMUNOLOGY; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOVASCULARIZATION, PATHOLOGIC; OVARIAN NEOPLASMS; PHYSIOLOGY; SCID MOUSE; SPECIES DIFFERENCE; VASCULARIZATION;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; ENDOTHELIAL CELLS; FEMALE; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MEMBRANE PROTEINS; MICE; MICE, SCID; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; NEOVASCULARIZATION, PATHOLOGIC; OVARIAN NEOPLASMS; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION; SPECIES SPECIFICITY; STROMAL CELLS; VASCULAR ENDOTHELIAL GROWTH FACTOR A; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84945927203     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-14-3773     Document Type: Article

References (46)

1. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999;284:770-6.
2. Bray SJ. Notchsignalling:asimple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-89.
3. Hofmann JJ, Iruela-Arispe ML. Notch signaling in blood vessels: who is talking to whom about what? Circ Res 2007;100:1556-68.
4. Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell 2009;16:196-208.
5. Roca C, Adams RH. Regulation of vascular morphogenesis by Notch signaling. Genes Dev 2007;21:2511-24.
6. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 2007;445:776-80.
7. Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J. Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 2007;134:839-44.
8. Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopou-los GD, et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A 2007;104: 3219-24.
9. Sainson RC, Aoto J, Nakatsu MN, Holderfield M, Conn E, Koller E, et al. Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 2005;19: 1027-9.
10. Siekmann AF, Lawson ND. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 2007;445:781-4.
11. Suchting S, Freitas C, leNoble F, Benedito R, Breant C, Duarte A, et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci U S A 2007;104:3225-30.
12. Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 2008;454:656-60.
13. Li JL, Sainson RC, Shi W, Leek R, Harrington LS, Preusser M, et al. Deltalike 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 2007;67:11244-53.
14. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 2006;444:1032-7.
15. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 2006;444:1083-7.
16. Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 2007;109: 4753-60.
17. Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 2004;82:341-58.
18. Jubb AM, Soilleux EJ, Turley H, Steers G, Parker A, Low I, et al. Expression of vascular notch ligand delta-like 4 and inflammatory markers in breast cancer. Am J Pathol 2010;176:2019-28.
19. Jubb AM, Turley H, Moeller HC, Steers G, Han C, Li JL, et al. Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer. Br J Cancer 2009;101:1749-57.
20. Mailhos C, Modlich U, Lewis J, Harris A, Bicknell R, Ish-Horowicz D. Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 2001;69:135-44.
21. Patel NS, Dobbie MS, Rochester M, Steers G, Poulsom R, Le Monnier K, et al. Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer. Clin Cancer Res 2006;12:4836-44.
22. Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 2005; 65:8690-7.
23. Hu W, Lu C, Dong HH, Huang J, Shen DY, Stone RL, et al. Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer Res 2011;71:6030-9.
24. Liu J, Matulonis UA. Anti-angiogenic agents in ovarian cancer: dawn of a new era? Curr Oncol Rep 2011;13:450-8.
25. Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 2006;3:24-40.
26. 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 2005;8:299-309.
27. Kerbel RS, Yu J, Tran J, Man S, Viloria-Petit A, Klement G, et al. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev 2001;20:79-86.
28. Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 1996;16:952-9.
29. Nakatsu MN, Hughes CC. An optimized three-dimensional in vitro model for the analysis of angiogenesis. Methods Enzymol 2008;443: 65-82.
30. Nakatsu MN, Sainson RC, Aoto JN, Taylor KL, Aitkenhead M, Perez-del-Pulgar S, et al. Angiogenic sprouting and capillary lumen formation modeled by human umbilical vein endothelial cells (HUVEC) in fibrin gels: the role of fibroblasts and Angiopoietin-1. Microvasc Res 2003; 66:102-12.
31. Kluk MJ, Ashworth T, Wang H, Knoechel B, Mason EF, Morgan EA, et al. Gauging NOTCH1 activation in cancer using immunohistochemistry. PLoS One 2013;8:e67306.
32. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32:1302-8.
33. Hu L, Hofmann J, Holash J, Yancopoulos GD, Sood AK, Jaffe RB. Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res 2005;11:6966-71.
34. Liu Z, Turkoz A, Jackson EN, Corbo JC, Engelbach JA, Garbow JR, et al. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J Clin Invest 2011;121:800-8.
35. Yan M, Callahan CA, Beyer JC, Allamneni KP, Zhang G, Ridgway JB, et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 2010;463: E6-7.
36. Miles KM, Seshadri M, Ciamporcero E, Adelaiye R, Gillard B, Sotomayor P, et al. Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts. PLoS One 2014;9: e112371.
37. Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 2009;5:168-77.
38. Kaelin WG Jr. Molecular biology. Use and abuse of RNAi to study mammalian gene function. Science 2012;337:421-2.
39. Butler JM, Kobayashi H, Rafii S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 2010;10:138-46.
40. Rose SL, Kunnimalaiyaan M, Drenzek J, Seiler N. Notch 1 signaling is active in ovarian cancer. Gynecol Oncol 2010;117:130-3.
41. Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 2005;15:102-11.
42. Li JL, Sainson RC, Oon CE, Turley H, Leek R, Sheldon H, et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res 2011;71:6073-83.
43. Thurston G, Kitajewski J. VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer 2008;99:1204-9.
44. Li JL, Jubb AM, Harris AL. Targeting DLL4 in tumors shows preclinical activity but potentially significant toxicity. Future Oncol 2010;6: 1099-103.
45. Djokovic D, Trindade A, Gigante J, Badenes M, Silva L, Liu R, et al. Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis. BMC Cancer 2010; 10:641.
46. Chiorean EG, LoRusso P, Strother RM, Diamond JR, Younger A, Messersmith WA, et al. A phase I first-in-human study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clin Cancer Res 2015;21:2695-703.