Angiogenesis Inhibition Via Thrombin Protease Activity (BIDMC 684)

Category:    Therapeutics - Methods

KeyWords:  Angiogenesis;  Cancer;  

BIDMC ID:    684

Abstract:

Background: Angiogenesis, the growth of new blood vessels, occurs naturally in mammals for healing wounds and for restoring blood flow to tissues after injury. When angiogenic stimulating factors are produced in excess of angiogenesis inhibitors, neovascularisation is favored. Conversely, when inhibitors are present in excess of stimulators, angiogenesis is stopped. Angiogenesis associated diseases include cancer, HIV, Kaposi’s sarcoma, rheumatoid arthritis, psoriasis, diabetic retinopathy, scleroderma and more. Considerable data point to the importance of angiogenesis both in primary tumor growth and metastases formation. Consequently angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Invention: The inventors discovered a novel function of thrombin, a protein involved in coagulation, as an anti-angiogenic molecule. Thrombin activates the so-called Protease Activated Receptors (PAR-1) on endothelial cells by triggering an anti-angiogenic response. Thus methods for generating thrombin, without causing coagulation, or events downstream of thrombin binding to the PARs could be used as anti-angiogenic therapy for numerous conditions, which are angiogenesis dependent. The inventors propose three ways to do this: 1. The use of PAR peptide agonists delivered systematically or locally, 2. The use of systemic or locally administered tissue plasminogen activator(tPA), and 3. The use of mutant form of urokinase (uPAm)that lacks the ability to bind to the uPA receptor. In order for tumors to increase in size, they must be able to recruit new blood vessels. The present invention features methods of inhibiting angiogenesis, with implications as a cancer therapy These methods are based on the discovery that activated thrombin has anti-angiogenic activity and that this anti-angiogenic activity is at least in part, mediated through the activation of a class of thrombin receptors termed, PAR-1.

Inventor:   Vikas P. Sukhatme MD PhD. Jaime Merchan MD. Barden Chan PhD.

Commercial Opportunity:

Angiogenesis associated diseases include cancer, HIV, Kaposi’s sarcoma, rheumatoid arthritis, psoriasis, diabetic retinopathy, scleroderma and more. Considerable data point to the importance of angiogenesis both in primary tumor growth and metastases formation. Consequently angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion

Competitive Advantages:

Though some of the anti-angiogenesis protein fragments are in clinical trials, they are difficult to produce and are not orally available. Peptides, such as those suggested by the inventors, should be cheaper and easier to produce. Furthermore, a drug that targets PAR-1, in addition to being antiangiogenic, could potentially be antitumor, since several human tumors overexpress PAR-1 on their surface.

Related Publications:

State of Development:

As the concentration of thrombin was increased on endothelial cells in culture, the inventors detected a switch from a stimulatory to inhibitory state. This biphasic property was also reported when the effects of thrombin were assessed in either in-vitro
endothelial cell tube formation or in an in-vivo chick choriollantoic membrane assay.

Related Technology URL:

Patent Status:

Worldwide right pending

TVO Contact Info:
     Christine Jost
     Associate Director TVO
     cjost@bidmc.harvard.edu
     Phone: 617-667-4239   Fax: 617-667-0646

     Beth Israel Deaconess Medical Center
     Technology Ventures Office  Room: BR-0200
     330 Brookline Avenue
     Boston, MA 02215