ABOUT THE RESEARCHER

OVERVIEW

Overview

Lab: damatolab.com

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.

 

Selected Publications

  • D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Nat Acad Sci USA 1994; 91: 4082-4085.

First demonstration that thalidomide is an angiogenesis inhibitor. It provided an explanation of the cause of thalidomide induced birth defects and proposed therapeutic potential for the drug for the treatment of cancer. In a later manuscript, we showed that thalidomide inhibits cancer growth in rabbits. As a result of this work thalidomide is now FDA approved as an oral angiogenesis inhibitor of cancer in humans.

 

  • 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.

We identified the first endogenous chemical which binds to and inhibits microtubules resulting in suppression of angiogenesis and cancer. In a later paper, we showed that oral 2-Methoxyestradiol inhibits cancer growth in mice. 2-Methoxyestradiol is currently in clinical trials for the inhibition of angiogenesis in the treatment of cancer and rheumatoid arthritis.

 

  • 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.

First demonstration that multiple components of the female reproductive system, such as ovulation, implantation and endometrial hypertrophy could be blocked with an angiogenesis inhibitor. We also proposed that this could be used to treat endometriosis, which we subsequently showed in later manuscripts.

 

  • 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.

Utilizing inbred stains of mice, we first demonstrated genetic differences in angiogenic potential. This supported the concept that genetic control of angiogenic responsiveness contributes significantly to the observed variation in the progression of numerous angiogenic diseases such as age related macular degeneration (ARMD).

 

  • 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.

We demonstrated that the exposure of the choroid to an overexpression of VEGF resulted in intrachoroidal neovascularization but not classic subretinal neovascularization as seen in ARMD. This supported a two hit model for CNV in ARMD, requiring both damage to Bruch’s membrane and an angiogenic stimuli.

 

  • 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

We discovered that more potent antiangiogenic analogs of thalidomide could be created by the addition of an amino side group to the aromatic ring of thalidomide. We initiated the first clinical trial with amino-thalidomide (ENMD-0095) in the US in 2002. These analogs were subsequently licensed by Celgene. Two different amino substituted thalidomide analogs, Revlimid (amino-EM12) and Pomalyst (amino-thalidomide, Pomalidomide) have been approved by the FDA for the treatment of Multiple Myeloma.


 

  • 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.

We characterized a novel model of human tumor dormancy employing GFP labeled human tumors that form occult microscopic foci which stay dormant in immunodeficient mice for over 8+ months. Using this model, we showed that escape from tumor dormancy can be triggered by the induction of angiogenesis.

 

  • 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.

We mapped the alterations in genetic regions that control the variation of angiogenic responsiveness to bFGF in mice. We have also mapped the VEGF loci in a separate manuscript. We are in the process of identifying the responsible polymorphisms.

 

  • Rogers MS, Birsner AE, D'Amato RJ. The mouse cornea micropocket angiogenesis assay. Nature Protocols 2(10):2545-50, 2007.

A review article detailing the protocol for the mouse corneal micropocket model which utilizes growth factors released from a slow release polymer to induce angiogenesis. This model was developed by us and has been used over the last decade as one of the gold standard assays in angiogenesis research.

 

  • 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.

We demonstrated that the nontoxic binding component of anthrax toxin (protective antigen) can be modified to produce a safe and potent angiogenesis inhibitor with anticancer activity. We showed that the receptors on endothelial cells, which serve as the entry sites for anthrax toxin, are normally used by endothelial cells to bind to the extracellular matrix during cell migration. By blocking these receptors, we interfered with endothelial migration and angiogenesis.

 

  • 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.

We mapped the alterations in genetic regions that control the variation of angiogenic responsiveness of laser induced choroidal neovasularization in mice.

  • 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.

We elucidated the mechanism by which African Americans have a much lower rate (when compared to Caucasians) of blinding new vessel growth under the retina in Age related Macular Degeneration. Melanocytes in Caucasians make high amounts of a novel angiogenic factor, called Fibromodulin, which is only produced in low amounts in African-Americans. 

PUBLICATIONS

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  1. Low dose amiodarone reduces tumor growth and angiogenesis. Sci Rep. 2020 10 22; 10(1):18034. View abstract
  2. Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes. Angiogenesis. 2021 02; 24(1):111-127. View abstract
  3. 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
  4. MicroRNA-18a-5p Administration Suppresses Retinal Neovascularization by Targeting FGF1 and HIF1A. Front Pharmacol. 2020; 11:276. View abstract
  5. PR1P ameliorates neurodegeneration through activation of VEGF signaling pathway and remodeling of the extracellular environment. Neuropharmacology. 2019 04; 148:96-106. View abstract
  6. Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. J Clin Invest. 2018 08 31; 128(9):4025-4043. View abstract
  7. Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice. PLoS Genet. 2017 Jun; 13(6):e1006848. View abstract
  8. A novel strategy to enhance angiogenesis in vivo using the small VEGF-binding peptide PR1P. Angiogenesis. 2017 Aug; 20(3):399-408. View abstract
  9. Cellular mechanism of oral absorption of solidified polymer micelles. Nanomedicine. 2015 Nov; 11(8):1993-2002. View abstract
  10. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential. FASEB J. 2015 Feb; 29(2):662-70. View abstract
  11. Characterization of a spontaneous retinal neovascular mouse model. PLoS One. 2014; 9(9):e106507. View abstract
  12. The corneal micropocket assay: a model of angiogenesis in the mouse eye. J Vis Exp. 2014 Aug 16; (90). View abstract
  13. Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment. J Clin Invest. 2014 Jan; 124(1):425-36. View abstract
  14. 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
  15. Suppression of autoimmune retinal inflammation by an antiangiogenic drug. PLoS One. 2013; 8(6):e66219. View abstract
  16. The albino mutation of tyrosinase alters ocular angiogenic responsiveness. Angiogenesis. 2013 Jul; 16(3):639-46. View abstract
  17. 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
  18. 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
  19. Common polymorphisms in angiogenesis. Cold Spring Harb Perspect Med. 2012 Nov 01; 2(11). View abstract
  20. The classical pink-eyed dilution mutation affects angiogenic responsiveness. PLoS One. 2012; 7(5):e35237. View abstract
  21. VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis. 2012 Jun; 15(2):265-73. View abstract
  22. Forty-year journey of angiogenesis translational research. Sci Transl Med. 2011 Dec 21; 3(114):114rv3. View abstract
  23. Unilateral sporadic retinal dysplasia: results of histopathologic, immunohistochemical, chromosomal, genetic, and VEGF-A analyses. J AAPOS. 2011 Dec; 15(6):579-86. View abstract
  24. A morphometric study of mechanotransductively induced dermal neovascularization. Plast Reconstr Surg. 2011 Oct; 128(4):288e-299e. View abstract
  25. 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
  26. Circulating endothelial progenitor cells are up-regulated in a mouse model of endometriosis. Am J Pathol. 2011 Apr; 178(4):1782-91. View abstract
  27. Angiogenesis in wounds treated by microdeformational wound therapy. Ann Surg. 2011 Feb; 253(2):402-9. View abstract
  28. Broad spectrum antiangiogenic treatment for ocular neovascular diseases. PLoS One. 2010 Sep 01; 5(9). View abstract
  29. Tumor growth and angiogenesis are dependent on the presence of immature dendritic cells. FASEB J. 2010 May; 24(5):1411-8. View abstract
  30. Genetic loci that control the size of laser-induced choroidal neovascularization. FASEB J. 2009 Jul; 23(7):2235-43. View abstract
  31. Matrigel cytometry: a novel method for quantifying angiogenesis in vivo. J Immunol Methods. 2009 Mar 15; 342(1-2):78-81. View abstract
  32. Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability. FASEB J. 2008 Oct; 22(10):3728-35. View abstract
  33. An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat Biotechnol. 2008 Jul; 26(7):799-807. View abstract
  34. 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
  35. Dendritic cells augment choroidal neovascularization. Invest Ophthalmol Vis Sci. 2008 Aug; 49(8):3666-70. View abstract
  36. 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
  37. Mutant anthrax toxin B moiety (protective antigen) inhibits angiogenesis and tumor growth. Cancer Res. 2007 Oct 15; 67(20):9980-5. View abstract
  38. Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis. FASEB J. 2008 Feb; 22(2):522-9. View abstract
  39. Angiogenesis and antiangiogenic therapy in endometriosis. Microvasc Res. 2007 Sep-Nov; 74(2-3):121-30. View abstract
  40. Chronic suppression of angiogenesis following radiation exposure is independent of hematopoietic reconstitution. Cancer Res. 2007 Mar 01; 67(5):2040-5. View abstract
  41. The mouse cornea micropocket angiogenesis assay. Nat Protoc. 2007; 2(10):2545-50. View abstract
  42. Antiangiogenic effect of oral 2-methoxyestradiol on choroidal neovascularization in mice. Exp Eye Res. 2006 Nov; 83(5):1102-7. View abstract
  43. A novel noninvasive model of endometriosis for monitoring the efficacy of antiangiogenic therapy. Am J Pathol. 2006 Jun; 168(6):2074-84. View abstract
  44. The effect of genetic diversity on angiogenesis. Exp Cell Res. 2006 Mar 10; 312(5):561-74. View abstract
  45. 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
  46. 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
  47. Endostatin inhibits the growth of endometriotic lesions but does not affect fertility. Fertil Steril. 2005 Oct; 84 Suppl 2:1144-55. View abstract
  48. X-linked dominant growth suppression of transplanted tumors in C57BL/6J-scid mice. Cancer Res. 2005 Jul 01; 65(13):5690-5. View abstract
  49. 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
  50. Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model. Fertil Steril. 2005 Jan; 83(1):171-81. View abstract
  51. Exogenous control of mammalian gene expression through modulation of RNA self-cleavage. Nature. 2004 Sep 23; 431(7007):471-6. View abstract
  52. Genetic loci that control the angiogenic response to basic fibroblast growth factor. FASEB J. 2004 Jul; 18(10):1050-9. View abstract
  53. Genetic loci that control vascular endothelial growth factor-induced angiogenesis. FASEB J. 2003 Nov; 17(14):2112-4. View abstract
  54. 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
  55. 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
  56. 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
  57. 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
  58. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol. 2001 Dec; 28(6):597-601. View abstract
  59. 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
  60. Rapid ocular angiogenic control via naked DNA delivery to cornea. Invest Ophthalmol Vis Sci. 2001 Aug; 42(9):1975-9. View abstract
  61. 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
  62. 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
  63. 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
  64. Angiogenic potential of prostate carcinoma cells overexpressing bcl-2. J Natl Cancer Inst. 2001 Feb 07; 93(3):208-13. View abstract
  65. 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
  66. Genetic heterogeneity of angiogenesis in mice. FASEB J. 2000 May; 14(7):871-6. View abstract
  67. 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
  68. 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
  69. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits. Br J Cancer. 1999 Jan; 79(1):114-8. View abstract
  70. Involvement of platelets in tumour angiogenesis? Lancet. 1998 Nov 28; 352(9142):1775-7. View abstract
  71. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. Diabetes. 1997 Oct; 46(10):1619-26. View abstract
  72. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res. 1997 Jun; 64(6):971-8. View abstract
  73. 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
  74. 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
  75. New activity of spironolactone. Inhibition of angiogenesis in vitro and in vivo. Circulation. 1996 Nov 15; 94(10):2566-71. View abstract
  76. Experimental corneal neovascularisation using sucralfate and basic fibroblast growth factor. Aust N Z J Ophthalmol. 1996 Aug; 24(3):289-95. View abstract
  77. A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci. 1996 Jul; 37(8):1625-32. View abstract
  78. 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
  79. Angiogenesis inhibition in age-related macular degeneration. Ophthalmology. 1995 Sep; 102(9):1261-2. View abstract
  80. Shedding light on diabetic retinopathy. Ophthalmology. 1995 Aug; 102(8):1127-8. View abstract
  81. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst. 1995 Apr 19; 87(8):581-6. View abstract
  82. 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
  83. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994 Apr 26; 91(9):4082-5. View abstract
  84. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994 Jan; 35(1):101-11. View abstract
  85. 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
  86. 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
  87. 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
  88. Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. Nature. 1987 May 28-Jun 3; 327(6120):324-6. View abstract
  89. Predicting Parkinson's disease. Nature. 1985 Sep 19-25; 317(6034):198-9. View abstract