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Related Research Units

Vascular Biology Program Research

Research Overview

In 1994, Dr. D'Amato discovered that thalidomide was a potent inhibitor of angiogenesis. This provided an explanation for the drug's notorious ability to cause birth defects. He then showed in a rabbit cancer model that thalidomide suppressed tumor growth in animals. Interestingly, he later found that a subset of anti-inflammatory drugs, such as sulindac and dexamethasone, had moderate anti-angiogenic activity. When these anti-inflammatory anti-angiogenic drugs were combined with thalidomide they increased both thalidomide's anti-angiogenic and anti-tumor activity. Based on these discoveries, numerous cancer clinical trials for thalidomide were initiated with and without dexamethasone. Thalidomide combined with dexamethasone was later approved by the FDA for the treatment of multiple myeloma.

His lab has since discovered more potent derivatives of thalidomide. These agents inhibit both angiogenesis and directly suppress the proliferation of neoplastic B-cells. The dual activity of these analogues make them more efficacious than thalidomide in vitro and in vivo. In animal studies, these next generation thalidomide analogues are more powerful anti-myeloma agents with reduced toxicity to normal bone marrow cells. The most potent of these analogues, Pomalidomide, has passed through phase III trials in humans and has been approved by the FDA.

Dr. D'Amato's current research focuses on the genetic control of angiogenesis and the development of new therapeutic agents, especially for the treatment of eye disease. His laboratory is exploring the role of genetics in determining an individual's angiogenic responsiveness. He has found that different strains of inbred mice have an approximately 10-fold range of response to growth factor stimulated angiogenesis in the corneal micropocket assay. These results suggest the presence of genetic factors that control individual angiogenic potential. He has used recombinant inbred strains and genetic mapping techniques to identify the chromosomal location of the ocular angiogenesis modifying loci. The laboratory is currently screening candidate genes and performing positional cloning techniques to isolate the responsible genes. By identifying the genetic determinates of angiogenic responsiveness within inbred mouse strains, he hopes to further understand the factors that regulate ocular angiogenesis in humans.

 

Robert D'Amato received his B.A, M.D. and Ph.D. from Johns Hopkins University. He completed his Ophthalmology residency at Harvard Medical School and the Massachusetts Eye and Ear Infirmary, and then went on to a postdoctoral research fellowship in the Folkman laboratories from 1992-1994. He has been an independent investigator at Children’s since 1994.

Research Background

Selected Publications

  1. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Nat Acad Sci USA 1994; 91: 4082-4085.
  2. D'Amato RJ, Lin CM, Flynn E, Folkman J Hamel E. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Nat Acad Sci USA 1994; 91: 3964-3968.
  3. Klauber N, Rohan R, Flynn E, D'Amato RJ. Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470. Nature Med 3(4): 443-446, 1997.
  4. Rohan RM, Fernandez A, Udagawa T, Yuan J and D'Amato RJ. Genetic heterogeneity of angiogenesis in mice. FASEB Journal 14(7):871-6, 2000.
  5. Schwesinger C, Yee C, Rohan R, Joussen A, Fernandez A, Meyer T, Poulaki V, Ma J, Redmond TM, Liu S, Adamis A, D'Amato RJ. Intrachoroidal Neovascularization in Transgenic Mice Overexpressing Vascular Endothelial Growth Factor in the Retinal Pigment Epithelium. Amer J Pathol 158(3) 1-11, 2001.
  6. Lentzsch S, Rogers MS, LeBlanc R, Birsner AE, Shah JH, Treston AM, Anderson KC, D'Amato RJ. S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice. Cancer Res 15;62(8):2300-5, 2002
  7. Udagawa T, Fernandez A, Achilles e, Folkman J, D'Amato RJ. Persistence of microscopic human cancers in mice: Alterations in the angiogenic balance accompanies loss of dormancy. FASEB Journal 16:1361-70, 2002.
  8. Rogers M, Rohan R, Birsner A, D'Amato RJ. Genetic loci that control the angiogenic response to basic fibroblast growth factor. FASEB Journal 18(10):1050-1059, 2004.
  9. Rogers MS, Birsner AE, D'Amato RJ. The mouse cornea micropocket angiogenesis assay. Nature Protocols 2(10):2545-50, 2007.
  10. Rogers MS, Christensen KA, Birsner AE, Short SM, Wigelsworth DJ, Collier RJ, D'Amato RJ. Mutant anthrax toxin B moiety (protective antigen) inhibits angiogenesis and tumor growth. Cancer Res Oct 15;67(20):9980-5, 2007.
  11. Nakai K, Rogers M, Baba T, Funakoshi T, Birsner A, Luyindula D, and D'Amato RJ. Genetic loci that control the size of laser-induced choroidal neovascularization. FASEB Journal 23(7):2235-43, 2009.
  12. Adini I, Ghosh K, Adini A, Chi ZL, Yoshimura T, Benny O, Connor KM, Rogers MS, Bazinet L, Birsner AE, Bielenberg DR, D'Amato RJ. Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment. J Clin Invest. Jan 2;124(1):425-36, 2014.

Publications

  1. Strigolactone decreases cadmium concentrations by regulating cadmium localization and glyoxalase defense system: Effects on nodules organic acids and soybean yield. Chemosphere. 2023 Sep; 335:139028. View Abstract
  2. Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma. J Clin Invest. 2022 12 01; 132(23). View Abstract
  3. Anti-angiogenic properties of microRNA-29a in preclinical ocular models. Proc Natl Acad Sci U S A. 2022 11 08; 119(45):e2204795119. View Abstract
  4. The Prominin-1-Derived Peptide Improves Cardiac Function Following Ischemia. Int J Mol Sci. 2021 May 13; 22(10). View Abstract
  5. Identification of Basp1 as a novel angiogenesis-regulating gene by multi-model system studies. FASEB J. 2021 05; 35(5):e21404. View Abstract
  6. Low dose amiodarone reduces tumor growth and angiogenesis. Sci Rep. 2020 10 22; 10(1):18034. View Abstract
  7. Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes. Angiogenesis. 2021 02; 24(1):111-127. View Abstract
  8. A Method for Developing Novel 3D Cornea-on-a-Chip Using Primary Murine Corneal Epithelial and Endothelial Cells. Front Pharmacol. 2020; 11:453. View Abstract
  9. MicroRNA-18a-5p Administration Suppresses Retinal Neovascularization by Targeting FGF1 and HIF1A. Front Pharmacol. 2020; 11:276. View Abstract
  10. PR1P ameliorates neurodegeneration through activation of VEGF signaling pathway and remodeling of the extracellular environment. Neuropharmacology. 2019 04; 148:96-106. View Abstract
  11. Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. J Clin Invest. 2018 08 31; 128(9):4025-4043. View Abstract
  12. Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice. PLoS Genet. 2017 Jun; 13(6):e1006848. View Abstract
  13. A novel strategy to enhance angiogenesis in vivo using the small VEGF-binding peptide PR1P. Angiogenesis. 2017 Aug; 20(3):399-408. View Abstract
  14. Cellular mechanism of oral absorption of solidified polymer micelles. Nanomedicine. 2015 Nov; 11(8):1993-2002. View Abstract
  15. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential. FASEB J. 2015 Feb; 29(2):662-70. View Abstract
  16. Characterization of a spontaneous retinal neovascular mouse model. PLoS One. 2014; 9(9):e106507. View Abstract
  17. The corneal micropocket assay: a model of angiogenesis in the mouse eye. J Vis Exp. 2014 Aug 16; (90). View Abstract
  18. Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment. J Clin Invest. 2014 Jan; 124(1):425-36. View Abstract
  19. Pomalidomide is strongly antiangiogenic and teratogenic in relevant animal models. Proc Natl Acad Sci U S A. 2013 Dec 10; 110(50):E4818. View Abstract
  20. Suppression of autoimmune retinal inflammation by an antiangiogenic drug. PLoS One. 2013; 8(6):e66219. View Abstract
  21. The albino mutation of tyrosinase alters ocular angiogenic responsiveness. Angiogenesis. 2013 Jul; 16(3):639-46. View Abstract
  22. Vascular endothelial growth factor C is increased in endometrium and promotes endothelial functions, vascular permeability and angiogenesis and growth of endometriosis. Angiogenesis. 2013 Jul; 16(3):541-51. View Abstract
  23. The stem cell marker prominin-1/CD133 interacts with vascular endothelial growth factor and potentiates its action. Angiogenesis. 2013 Apr; 16(2):405-16. View Abstract
  24. Common polymorphisms in angiogenesis. Cold Spring Harb Perspect Med. 2012 Nov 01; 2(11). View Abstract
  25. The classical pink-eyed dilution mutation affects angiogenic responsiveness. PLoS One. 2012; 7(5):e35237. View Abstract
  26. VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis. 2012 Jun; 15(2):265-73. View Abstract
  27. Forty-year journey of angiogenesis translational research. Sci Transl Med. 2011 Dec 21; 3(114):114rv3. View Abstract
  28. Unilateral sporadic retinal dysplasia: results of histopathologic, immunohistochemical, chromosomal, genetic, and VEGF-A analyses. J AAPOS. 2011 Dec; 15(6):579-86. View Abstract
  29. A morphometric study of mechanotransductively induced dermal neovascularization. Plast Reconstr Surg. 2011 Oct; 128(4):288e-299e. View Abstract
  30. Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in experimental endometriosis in vivo. Fertil Steril. 2011 Oct; 96(4):1021-8. View Abstract
  31. Circulating endothelial progenitor cells are up-regulated in a mouse model of endometriosis. Am J Pathol. 2011 Apr; 178(4):1782-91. View Abstract
  32. Angiogenesis in wounds treated by microdeformational wound therapy. Ann Surg. 2011 Feb; 253(2):402-9. View Abstract
  33. Broad spectrum antiangiogenic treatment for ocular neovascular diseases. PLoS One. 2010 Sep 01; 5(9). View Abstract
  34. Tumor growth and angiogenesis are dependent on the presence of immature dendritic cells. FASEB J. 2010 May; 24(5):1411-8. View Abstract
  35. Genetic loci that control the size of laser-induced choroidal neovascularization. FASEB J. 2009 Jul; 23(7):2235-43. View Abstract
  36. Matrigel cytometry: a novel method for quantifying angiogenesis in vivo. J Immunol Methods. 2009 Mar 15; 342(1-2):78-81. View Abstract
  37. Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability. FASEB J. 2008 Oct; 22(10):3728-35. View Abstract
  38. An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat Biotechnol. 2008 Jul; 26(7):799-807. View Abstract
  39. Differential suppression of vascular permeability and corneal angiogenesis by nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci. 2008 Sep; 49(9):3909-13. View Abstract
  40. Dendritic cells augment choroidal neovascularization. Invest Ophthalmol Vis Sci. 2008 Aug; 49(8):3666-70. View Abstract
  41. 2-methoxyestradiol inhibits hypoxia-inducible factor-1{alpha} and suppresses growth of lesions in a mouse model of endometriosis. Am J Pathol. 2008 Feb; 172(2):534-44. View Abstract
  42. Mutant anthrax toxin B moiety (protective antigen) inhibits angiogenesis and tumor growth. Cancer Res. 2007 Oct 15; 67(20):9980-5. View Abstract
  43. Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis. FASEB J. 2008 Feb; 22(2):522-9. View Abstract
  44. Angiogenesis and antiangiogenic therapy in endometriosis. Microvasc Res. 2007 Sep-Nov; 74(2-3):121-30. View Abstract
  45. Chronic suppression of angiogenesis following radiation exposure is independent of hematopoietic reconstitution. Cancer Res. 2007 Mar 01; 67(5):2040-5. View Abstract
  46. The mouse cornea micropocket angiogenesis assay. Nat Protoc. 2007; 2(10):2545-50. View Abstract
  47. Antiangiogenic effect of oral 2-methoxyestradiol on choroidal neovascularization in mice. Exp Eye Res. 2006 Nov; 83(5):1102-7. View Abstract
  48. A novel noninvasive model of endometriosis for monitoring the efficacy of antiangiogenic therapy. Am J Pathol. 2006 Jun; 168(6):2074-84. View Abstract
  49. The effect of genetic diversity on angiogenesis. Exp Cell Res. 2006 Mar 10; 312(5):561-74. View Abstract
  50. Analysis of tumor-associated stromal cells using SCID GFP transgenic mice: contribution of local and bone marrow-derived host cells. FASEB J. 2006 Jan; 20(1):95-102. View Abstract
  51. Short synthetic endostatin peptides inhibit endothelial migration in vitro and endometriosis in a mouse model. Fertil Steril. 2006 Jan; 85(1):71-7. View Abstract
  52. Endostatin inhibits the growth of endometriotic lesions but does not affect fertility. Fertil Steril. 2005 Oct; 84 Suppl 2:1144-55. View Abstract
  53. X-linked dominant growth suppression of transplanted tumors in C57BL/6J-scid mice. Cancer Res. 2005 Jul 01; 65(13):5690-5. View Abstract
  54. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell. 2005 Jan; 7(1):101-11. View Abstract
  55. Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model. Fertil Steril. 2005 Jan; 83(1):171-81. View Abstract
  56. Exogenous control of mammalian gene expression through modulation of RNA self-cleavage. Nature. 2004 Sep 23; 431(7007):471-6. View Abstract
  57. Genetic loci that control the angiogenic response to basic fibroblast growth factor. FASEB J. 2004 Jul; 18(10):1050-9. View Abstract
  58. Genetic loci that control vascular endothelial growth factor-induced angiogenesis. FASEB J. 2003 Nov; 17(14):2112-4. View Abstract
  59. Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice. Neoplasia. 2003 Jan-Feb; 5(1):32-40. View Abstract
  60. Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy. FASEB J. 2002 Sep; 16(11):1361-70. View Abstract
  61. S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice. Cancer Res. 2002 Apr 15; 62(8):2300-5. View Abstract
  62. Injection of antiangiogenic agents into the macaque preovulatory follicle: disruption of corpus luteum development and function. Endocrine. 2002 Apr; 17(3):199-206. View Abstract
  63. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol. 2001 Dec; 28(6):597-601. View Abstract
  64. Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 2001 Oct 15; 61(20):7669-74. View Abstract
  65. Rapid ocular angiogenic control via naked DNA delivery to cornea. Invest Ophthalmol Vis Sci. 2001 Aug; 42(9):1975-9. View Abstract
  66. Strain-dependent anterior segment neovascularization following intravitreal gene transfer of basic fibroblast growth factor (bFGF). J Gene Med. 2001 May-Jun; 3(3):252-9. View Abstract
  67. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc Natl Acad Sci U S A. 2001 Apr 10; 98(8):4605-10. View Abstract
  68. Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. Am J Pathol. 2001 Mar; 158(3):1161-72. View Abstract
  69. Angiogenic potential of prostate carcinoma cells overexpressing bcl-2. J Natl Cancer Inst. 2001 Feb 07; 93(3):208-13. View Abstract
  70. Cytochalasin E, an epoxide containing Aspergillus-derived fungal metabolite, inhibits angiogenesis and tumor growth. J Pharmacol Exp Ther. 2000 Aug; 294(2):421-7. View Abstract
  71. Genetic heterogeneity of angiogenesis in mice. FASEB J. 2000 May; 14(7):871-6. View Abstract
  72. Treatment of the Kasabach-Merritt syndrome with pegylated recombinant human megakaryocyte growth and development factor in mice: elevated platelet counts, prolonged survival, and tumor growth inhibition. Pediatr Res. 1999 Nov; 46(5):562-5. View Abstract
  73. The antiangiogenic agents TNP-470 and 2-methoxyestradiol inhibit the growth of angiosarcoma in mice. J Am Acad Dermatol. 1999 Jun; 40(6 Pt 1):925-9. View Abstract
  74. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits. Br J Cancer. 1999 Jan; 79(1):114-8. View Abstract
  75. Involvement of platelets in tumour angiogenesis? Lancet. 1998 Nov 28; 352(9142):1775-7. View Abstract
  76. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. Diabetes. 1997 Oct; 46(10):1619-26. View Abstract
  77. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res. 1997 Jun; 64(6):971-8. View Abstract
  78. Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470. Nat Med. 1997 Apr; 3(4):443-6. View Abstract
  79. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res. 1997 Jan 01; 57(1):81-6. View Abstract
  80. New activity of spironolactone. Inhibition of angiogenesis in vitro and in vivo. Circulation. 1996 Nov 15; 94(10):2566-71. View Abstract
  81. Experimental corneal neovascularisation using sucralfate and basic fibroblast growth factor. Aust N Z J Ophthalmol. 1996 Aug; 24(3):289-95. View Abstract
  82. A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci. 1996 Jul; 37(8):1625-32. View Abstract
  83. Interactions of 2-methoxyestradiol, an endogenous mammalian metabolite, with unpolymerized tubulin and with tubulin polymers. Biochemistry. 1996 Jan 30; 35(4):1304-10. View Abstract
  84. Angiogenesis inhibition in age-related macular degeneration. Ophthalmology. 1995 Sep; 102(9):1261-2. View Abstract
  85. Shedding light on diabetic retinopathy. Ophthalmology. 1995 Aug; 102(8):1127-8. View Abstract
  86. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst. 1995 Apr 19; 87(8):581-6. View Abstract
  87. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci U S A. 1994 Apr 26; 91(9):3964-8. View Abstract
  88. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994 Apr 26; 91(9):4082-5. View Abstract
  89. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994 Jan; 35(1):101-11. View Abstract
  90. Microscopic visualization of the retina by angiography with high-molecular-weight fluorescein-labeled dextrans in the mouse. Microvasc Res. 1993 Sep; 46(2):135-42. View Abstract
  91. The effect of age and initial visual acuity on the systemic and visual prognosis of central retinal vein occlusion. Aust N Z J Ophthalmol. 1991 May; 19(2):118-22. View Abstract
  92. Selective labeling of serotonin uptake sites in rat brain by [3H]citalopram contrasted to labeling of multiple sites by [3H]imipramine. J Pharmacol Exp Ther. 1987 Jul; 242(1):364-71. View Abstract
  93. Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. Nature. 1987 May 28-Jun 3; 327(6120):324-6. View Abstract
  94. Predicting Parkinson's disease. Nature. 1985 Sep 19-25; 317(6034):198-9. View Abstract

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