Cardiologists use heparin in treating coronary heart disease because itprolongs clotting time in human blood. Oncologists would like to useheparin because of its anti-cancer properties.

"Oncologists are interested in the fact that heparin-like molecules canmodulate growth factors," said tumor cell biologist David Roberts, ofthe National Cancer Institute (NCI) in Bethesda, Md. "But theproblem is, if you give these blood-thinning heparin-like molecules tocancer patients, they'll bleed to death.

"So the field would like to separate anticoagulant activity from theantiproliferative activity of these growth-factor antagonists," Robertsobserved. "Besides academic investigators," he recalled, "at least onecompany, Glycomed Inc., of Alameda, Calif., has been trying toseparate these two activities by making semisynthetic analogues ofheparin."

Roberts is chief of the NCI's Biochemical Pathology Section. He toldBioWorld Today, "Our strategy gives greater specificity, becausewe're using peptide antagonists that bind to the heparin instead ofanalogues of heparin itself."

He continued: "Our compounds don't work as anticoagulants, sowe're excluded from that market. But we have another way ofinhibiting heparin-dependent growth factors, which potentially avoidsthat side effect."

Heparin serves as a receptor for fibroblast growth factor (FGF), andfor thrombospondin, a multi-purpose molecule extracellular matrixprotein. "One of thrombospondin's best-characterized biologicaleffects on endothelial cells," Roberts observed, "is its ability toinhibit angiogenesis."

Any factor that can squelch the proliferation of new blood vesselsthat feed new or growing tumors is a potential boon to oncologists.(See BioWorld Today, Aug. 11, 1995, p. 1.)

"So the genesis of our invention," Roberts went on, "was based onidentifying active sequences in thrombospondin that could mimic theactivity of the whole protein."

Two recent U.S. patents, of which Roberts is principal inventor,define, and protect, peptides derived from thrombospondin:

* Patent No. 5,491,130, issued Feb. 13, 1996: "Peptide inhibitors offibronectin and related collagen-binding proteins."

* Patent No. 5,357,051 issued Oct. 18, 1994: "Heparin and sulfatide-binding peptides from . . . human thrombospondin."

These are the latest in a growing portfolio of patents covering thegrowing field of angiogenesis-inhibiting anti-cancer strategies.Kaposi's sarcoma, breast carcinoma and melanoma, Robertssuggested, are among the cancers most likely to respond to thistherapeutic approach.

Next: Diabetic Retinopathy And Rheumatoid Arthritis

He now sees his concept as metastasizing to other inflammatorydisease areas, notably diabetic retinopathy (see BioWorld Today,May 18, 1996, p. 1) and rheumatoid arthritis.

"Transforming growth factor beta [TGFb] also is modulated bythrombospondin and these peptides," Roberts noted. "Besidesinhibiting angiogenesis, as another of its activities, it's also a majorregulator of wound repair, fibrosis and immune responses. So thecommercial applications are largely in dealing with chronic wounds,and the converse side of that is inhibitors to reduce scarring, which isimportant for cosmetic therapy."

To this he added "a lot of inflammatory diseases, glomerularnephritis and inflammatory lung disease, where the ability to inhibitTGFb is of great interest to companies, because they want to be ableto reduce the damage in tissue scarring and proliferation ofconnective tissue, which are induced by that growth factor.

Roberts and his associates are conducting tumorigenesis studies inmice and rats, and preparing stable analogues for the original,patented peptides.

"One of our major advances recently," Roberts said, "is that we'veprepared retro-inverso analogues, going from the original peptides toa sort of first-generation peptidomimetic."

The trouble with such peptides intended as in vivo therapeutics, heexplained, is their very brief half-lives _ cut short by proteases in thebody.

"Retro-inverso," Roberts explained, "means made out of D-aminoacids backwards. So it's a mirror image of a mirror image.

"We've inverted the chirality of the amino acids, but by assemblingthem in the reverse order, we generate the same shape and space.Biological activity," he pointed out, "is based on its shape of themolecule. So if we can reproduce that activity with something that isstable, we can obtain greater half-life.

"This is the first application for growth-factor antagonists such asheparin and adhesive modulators such as fibronectin," he observed."That analogue has demonstrated activity in our animal studies."

He made the added point: "The commercial application of these leaddrug mimetics should be an attractive element for a companyawarded a CRADA to develop our basic research.

"In our experience they have very low toxicity, so as angiogenesismodulators they should have fewer side effects than conventionalcytotoxic chemotherapy of cancer.

"What's more, they are small molecules, which have the advantage oflower cost in preparing recombinant proteins as angiogenesisinhibitors.

At one time, Robert's NCI section had a letter of intent with PrizmPharmaceuticals Inc., of San Diego, for a CRADA to co-develop hispeptidomimetics. "That understanding has expired," Roberts said.

He now seeks in particular for his CRADA "a company dedicated tothe development of small therapeutic molecules, with in-houseexpertise related to peptide R&D."

Editor's note: An announcement of a CRADA opportunity "for theScientific and Commercial Development of Novel Heparin-BindingPeptides" appeared last week in the Federal Register dated June 18,1996. The deadline for CRADA applications is 90 days from thatpublication date. There is no time limit for patent licensingapplications.

For technical questions concerning this research, consult DavidRoberts, chief, Biochemical Pathology Section, NCI, (301) 496-6264; for CRADA information, Gary Colby, Office of TechnologyDevelopment, NCI; for licensing proposals, Carol Lavrich,Technology Licensing Specialist, Office of Technology Transfer,NIH, (301) 496-7735, ext. 287. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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