Cancer is a coming event that seldom casts its shadow before. Withhelp from industry, a newly discovered gene, and its protein, couldtelegraph a tumor's punch well before symptoms of malignancy blowthe cancer's cover.Last week's Federal Register advertised the National Cancer Institute'soffer of a Cooperative Research and Development Agreement(CRADA) for commercialization of "Monoclonal Antibodies to aTumor-Specific Growth Factor for the Diagnosis and Prognosis ofPremalignant Lesions and Cancer."The notice stipulates that bids from industry must be received by 5 p.m.Sept. 9. However, "depending on responses we receive by that date,"NCI's technical development specialist, Michael Christini, toldBioWorld Today, "later proposals may be accepted."Two scientists, one in Italy, the other at NCI's Laboratory of TumorImmunology and Biology, in Bethesda, Md., share title to the pendingU.S. patent on the novel gene, for which the designated CRADApartner will obtain a license.Co-inventor David Salamon, who heads the laboratory's tumor growthfactor section, told BioWorld Today: "The woman who cloned thegene is Graziella Persico, at the Institute of Genetics and Biophysics inNaples. She actually identified these sequences, serendipitously, bygetting a cDNA to another gene that was fused to their reading frame."Besides isolating the full-length genomic clone, Persico did thechromosome mapping, and named the gene cripto.NCI then "took and expanded" the Italian molecular geneticist'sdiscovery, Salamon added. "We did the biological studies in tumors,the over-expression in epithelial cells, trying to define the biology,where it's expressed, and what its function might be."A Protein In Search Of Its ReceptorCripto-1, mapped to the short arm of human chromosome 3, belongs toa family of genes and pseudogenes "within the epidermal growth factorfamily of proteins," Salamon explained. "It expresses a protein 188amino acids long, of which a 37-moiety domain resembles the motif ofepidermal growth factor (EGF)."When they further researched this protein, they found that it does notbind to the EGF receptor. Rather, the gene expresses the proteinspecifically in the early premalignant stages of breast, colon and,possibly, stomach carcinomas."It could be a model tumor marker," Salamon said, "a tumor-associatedantigen, but one that comes up early in the malignant conversionprocess." Its specificity, he added, ranges from about 50 percent of pre-cancerous gastric conditions to 80 percent of primary breast andcolorectal carcinomas. "In non-cancerous mammary and colonicepithelium, it's level of expression is very low, around 10 percent."NCI had signed a CRADA with Berlex Biosciences in 1991, Salamonrecalled, but it has since expired. So we're advertising for a newCRADA partner now to continue the research and development.A pharmaceutical or biotechnology company which signed on wouldfirst, he said, "produce a panel of murine antibodies raised againstsome recombinant EGF-related peptides. These monoclonals wouldhave a higher degree of specificity and sensitivity than the rabbitpolyclonals we now have. Their second order of business," hecontinued, "would be to get enough of the recombinant protein purifiedto identify a receptor for this protein."From Prognosis To Diagnosis To Therapy"Markers for premalignant lesions are few and far between," Salamonobserved. "What we have to offer a prospective corporate partner is notonly a tumor marker but an antigen for predicting and monitoring thepotential for conversion to more malignant stages from some of thesepremalignant conditions."He pointed out that, "In breast, such early-stage markers are virtuallynon-existent. For colon they are basically genetic markers with respectto tumor suppresser genes. And in stomach, nothing at all, to myknowledge."But beyond prognosis and diagnosis, Salamon sees a possibletherapeutic function for his cripto-1 gene and its growth-factor product:"This protein is expressed by a colon cancer cell line. If you block itsexpression, using an antisense approach, you can significantly inhibitthe growth of those tumor cells in cell culture and in nude mice, both ofwhich we've done."

[Editor's Note: For information concerning this CRADA opportunity,contact NCI technical development specialists Michael Christini, orMark Noel at (301) 496-0477.] n

-- David N. Leff Science Editor

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