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Inhibition of Cell Motility, Angiogenesis and Metastasis

Posted Jun 15 2010 5:00pm

Description of Invention:
The present invention relates to potent, highly selective antagonists of Grb2 Src homology-2 (SH2) domain binding. Grb2, through its SH2 domain, mediates growth factor driven cell motility in vitro and angiogenesis in vivo. These synthetic, small molecule antagonists have been shown to block cell motility stimulated by hepatocyte growth factor (HGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial cell growth factor (VEGF). They also potently inhibit HGF- and VEGF-stimulated morphogenesis and angiogenesis, respectively, in several model systems. HGF stimulates mitogenesis, motogenesis and morphogenesis in a wide range of cellular targets during development and adulthood, and its signaling pathway is frequently over-activated in human cancers, including colon, gastric, breast, lung, thyroid and renal carcinomas, melanoma, several sarcomas as well as glioblastoma. The ability of HGF to initiate a program of cell dissociation and increased cell motility coupled with increased protease production promotes aggressive cellular invasion and is frequently linked to tumor metastasis.

Metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates. The small, synthetic Grb2 SH2 domain antagonists described in this invention have been shown to inhibit the induced and spontaneous metastasis of melanoma- and prostate cancer-derived tumor cells in mice. These results establish a critical role for Grb2 SH2 domain-mediated interactions in the metastatic process and support the potential efficacy of this class of compound in reducing the metastatic spread of primary solid tumors in humans.

Inhibition of cell motility-dependent processes, including angiogenesis and metastasis, in several types of cancer such as prostate, colon, gastric, breast, lung, thyroid and renal carcinomas, melanoma and various sarcomas.

Development Status:
In vivo and in vitro studies have been conducted on this technology.

Donald P Bottaro (NCI)

Patent Status:
HHS, Reference No. E-265-1999/2
US, Application No. 11/525,672 filed 22 Sep 2006

Relevant Publication:
  1. Atabey N, Gao Y, Yao Z-J, Breckenridge D, Soon L, Soriano JV, Burke TR Jr, Bottaro DP. Potent blockade of Hepatocyte Growth Factor-stimulated cell motility, matrix invasion and branching morphogenesis by antagonists of Grb2 Src homology 2 domain interactions. J Biol Chem. 2001 Apr 27;276(17):14308-14314. [ PubMed abs ]
  2. Shi Z-D, Wei C-Q, Wang X, Lee K, Liu H, Zhang M, Vasselli J, Bottaro DP, Linehan WM, Yang D, Burke TR Jr. Macrocyclization in the design of tetra-tetrapeptide mimetics that display potent inhibition of Grb2 SH2 domain binding in whole cell systems. In: Peptide Revolution: Genomics, Proteomics Therapeutics. Chorev, M and Sawyer, TK, Eds. American Peptide Society, pp 515-517, 2003.
  3. Soriano JV, Lui N, Gao Y, Yao Z-J, Ishibashi T, Underhill C, Burke TR Jr, Bottaro DP. Inhibition of angiogenesis by growth factor receptor bound protein 2-Src homology 2 domain bound antagonists. Mol Cancer Ther. 2004 Oct;3(10):1289-1299. [ PubMed abs ]
  4. Shi Z-D, Karki RG, Worthy KM, Bindu LK, Dharmawardana PG, Nicklaus MC, Bottaro DP, Fisher RJ, Burke TR Jr. Utilization of a nitrobenzoxadiazole (NBD) fluorophore in the design of a Grb2 SH2 domain-binding peptide mimetic. Bioorg Med Chem Lett. 2005 Mar 1;15(5):1385-1388. [ PubMed abs ]
  5. Kang S-U, Shi, Z-D, Worthy KM, Bindu LK, Dharmawardana PG, Choyke SJ, Bottaro DP, Fisher RJ, Burke TR Jr. Examination of phosphoryl-mimicking functionalities within a macrocyclic Grb2 SH2 domain-binding platform. J Med Chem. 2005 Jun 16;48(12):3945-3948. [ PubMed abs ]
  6. Shi Z-D, Peruzzi B, Dharmawardana PG, Leech T, Appella E, Worthy KM, Bindu LK, Fisher RJ, Bottaro DP, Burke TR Jr. Synthesis and use of C-terminally biotinylated peptidomimetics with high Grb2 SH2 domain-binding affinity. In: Understanding Biology Using Peptides, Blondelle SE (Ed), American Peptide Society, pp 208-209, 2005.
  7. Dharmawardana PG, Peruzzi B, Giubellino A, Burke TR Jr, Bottaro DP. Molecular targeting of growth factor receptor-bound 2 (Grb-2) as an anti-cancer strategy. Anti-Cancer Drugs 2006 Jan;17(1):13-20. [ PubMed abs ]
  8. Liu F, Worthy KM, Bindu L, Giubellino A, Bottaro DP, Fisher RJ, Burke TR Jr. Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis. Org Biomol Chem. 2007 Jan 21;5(2):367-372. [ PubMed abs ]
  9. Giubellino A, Gao Y, Lee S, Lee M-J, Vasselli JR, Medepalli S, Trepel JB, Burke TR Jr, Bottaro DP. Inhibition of tumor metastasis by a growth factor receptor bound protein Src domain-binding antagonist. Cancer Res. (Priority Report) 2007 Jul 1;67(13):6012-6016. [ PubMed abs ]

Licensing Status:
Available for exclusive and non-exclusive licensing.

Collaborative Research Opportunity:
The Urologic Oncology Branch of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Grb2 SH2 domain antagonsists as anti-cancer drugs. Please contact John D. Hewes, Ph.D. at 301-435-3121 or for more information.

Cancer - Therapeutics
In-vivo Data
In-vitro Data

For Additional Information Please Contact:
Jennifer Wong
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4633
Fax: 301-402-0220

Ref No: 1755

Updated: 06/2010

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