REHOVOT, Israel - A collaboration between Israeli start-up InSight Ltd. and an academic group led by Israel Vlodavsky of the Hadassah-Hebrew University Hospital, in Jerusalem, has isolated, purified and sequenced the heparinase enzyme and cloned the gene coding for this protein, which is a key vector in the spread of cancer.

The most common route of cancer metastases involves invasion of tumor cells into blood vessels. The majority of newly diagnosed cancer patients already have the secondary tumors, but they are often undetectable.

“Many cancer-related deaths and virtually all those from colon and breast tumors are due to the dispersion and growth of secondary tumor cells and not to the primary tumor,“ said Vlodavsky, head of the tumor biology research unit in Hadassah's Ein Kerem campus department of oncology. During the past 15 years, he has analyzed the interaction of malignant cells with extracellular matrix and blood vessels, and has demonstrated that tumor cell invasiveness is directly correlated with heparinase activity - that is, the degradation of heparin sulfate, a major constituent of the blood vessel wall.

“During the past six months, working with the molecular biologists at InSight, we discovered that the heparinase gene is highly expressed in human tumors,“ said Vlodavsky, who is also chief scientist of InSight, in Rehovot.

InSight, a private company focusing on the development of recombinant proteins, genetically engineered the human polysaccharide cleaving enzyme, paving the way for the development of new therapeutic drugs.

The proprietary assets connected to this discovery include all aspects of gene expression, diagnostics and inhibitors of heparinase production.

“We see three main aspects developing at InSight from the initial discovery made just a couple of months ago,“ said Dror Melamed, operations manager of InSight.

One avenue is development of the recently cloned recombinant enzyme itself for therapeutic applications such as accelerated wound healing. Cleaving heparin sulfate may release and activate growth-promoting factors essential to the mending process.

A second avenue could be in cancer diagnostics, based on extensive results from animal models and in vitro research with heparinase.

“Work is in progress with antibodies we have developed for screens of cancer vs. normal cells,“ Melamed said. “In the broadest outlines we are seeking to identify and image the most aggressive tumors at the earliest stages. If we can confirm that this is a crucial enzyme synthesized early in metastasis, then we have a molecular probe for detection of micrometastases now clinically invisible, which could differentiate patients at more or less risk, and tailor their treatment accordingly.“

The third avenue is development of effective heparinase inhibitors that “could prevent metatastic tumor cells and activated T lymphocytes from leaving the circulatory system and reaching their targets,“ Vlodavsky said.

Using the heparinase inhibitor, InSight also has accumulated evidence from animal models of its autoimmune and anti-inflammatory activity, especially against multiple sclerosis.

“We have received a worldwide exclusive license to develop and commercialize novel heparin mimetics in collaboration with a research and development group of Rhone-Poulenc Rorer, with wide-reaching therapeutic potential,“ said Naim Tamari, managing director of InSight.

Rhone-Poulenc Rorer Inc., of Collegeville, Pa., is part of the Paris-based Rhone-Poulenc Group. *

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