Researcher | 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.
Researcher | Research Background
- D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Nat Acad Sci USA 1994; 91: 4082-4085.
- 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.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- Rogers MS, Birsner AE, D'Amato RJ. The mouse cornea micropocket angiogenesis assay. Nature Protocols 2(10):2545-50, 2007.
- 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.
- 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.
- 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.