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.

About Robert D'Amato

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.

Key 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. 

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Researcher Areas

  • Small Molecule Inhibitors of Angiogenesis
  • Age Related Macular Degeneration
  • Genetic Modifiers of Angiogenesis

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