This proposal continues a long-standing collaboration between the laboratories of Judah Folkman and Douglas Hanahan that has focussed on the mechanisms of tumor angiogenesis and therapeutic applications of such new knowledge. The long-term objectives are to identify the critical components of the regulatory machinery that is abrogated to switch angiogenesis on and to sustain it. The progress from this joint program has centrally implicated endogenous angiogenesis inhibitors in this misregulation, presenting both therapeutic and mechanistic opportunities. An emerging paradigm is that proteases are involved in many aspects of angiogenic regulation, ranging from excision of inhibitors embedded in larger proteins, to release of sequestered angiogenic growth factors. The two laboratories have synergistic, complementary expertise in protein biochemistry and endothelial cell biology and in molecular genetics and transgenic mouse models of carcinogenesis.
The specific aims are: 1. Develop a new organizing principle for discovery of endogenous angiogenesis inhibitors that exist as internal fragments of hemostatic proteins. 2. Determine the role of an exciting class of intercellular signaling molecules, the ephrins in the angiogenic switch and in specification of tumor vasculature. 3. Genetically define the key regulatory genes among candidate activators, inhibitors and metalloproteinases, for the angiogenic switch during multistage tumorigenesis in transgenic mouse models of endocrine, pancreatic, cutaneous and cervical carcinoma. 4. Further develop experimental therapeutic approaches that utilize angiogenesis inhibitors for treatment or prevention of endogenous cancers in transgenic mouse models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037395-21
Application #
6497605
Study Section
Pathology A Study Section (PTHA)
Program Officer
Mohla, Suresh
Project Start
1983-01-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
21
Fiscal Year
2002
Total Cost
$715,078
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Folkman, Judah (2006) Angiogenesis. Annu Rev Med 57:1-18
Satchi-Fainaro, Ronit; Mamluk, Roni; Wang, Ling et al. (2005) Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell 7:251-61
Sternlicht, M D; Werb, Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463-516
O'Reilly, M S; Brem, H; Folkman, J (1995) Treatment of murine hemangioendotheliomas with the angiogenesis inhibitor AGM-1470. J Pediatr Surg 30:325-9;discussion 329-30
Nguyen, M; Watanabe, H; Budson, A E et al. (1994) Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 86:356-61
Li, V W; Folkerth, R D; Watanabe, H et al. (1994) Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet 344:82-6
Nguyen, M; Watanabe, H; Budson, A E et al. (1993) Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J Natl Cancer Inst 85:241-2
Brem, H; Gresser, I; Grosfeld, J et al. (1993) The combination of antiangiogenic agents to inhibit primary tumor growth and metastasis. J Pediatr Surg 28:1253-7
Folkman, J; Szabo, S; Stovroff, M et al. (1991) Duodenal ulcer. Discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann Surg 214:414-25;discussion 426-7
Li, W W; Grayson, G; Folkman, J et al. (1991) Sustained-release endotoxin. A model for inducing corneal neovascularization. Invest Ophthalmol Vis Sci 32:2906-11

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