Cancers that run in families are customarily blamed on recessiveoncogenes. That is, the genetic defect occurs because mutated genes_ alleles _ inherited from both parents, result in turning off tumorsuppressor genes.
Now comes a finding that one known proto-oncogene, RET, causesnumerous familial cancers of dominant rather than recessive origin;it converts normal genes into transforming genes that make cellsmalignant.
Experimental oncologist Pier Paolo Di Fiore calls his unexpecteddeparture from the recessive norm "the first known example inhumans, indeed in mammalians, of a dominant oncogene transmittedthrough the germline in hereditary cancer."
He told BioWorld Today that it "provides the rationale for thinkingabout specific therapies."
Di Fiore leads a group at the National Cancer Institute's Laboratoryof Cellular and Molecular Biology. He is senior author of a paper intoday's Science. Its title: "Activation of RET as a dominanttransforming gene by germline mutations of MEN2A and MEN2B."
Meet The MEN Malignancy Syndrome
MEN stands for "multiple endocrine neoplasias;" it comes in twodegrees of gravity: MEN2A, Di Fiore explained, causespheochromocytoma, (a tumor of the adrenal glands),hyperthyroidism and familial medullary thyroid carcinoma. "This isnot the typical thyroid tumor," he said. "It does not affect the cells ofthe thyroid, but its so-called C cells, which produce calcitonin in thegland." Calcitonin is a hormone that deals with calcium metabolism.
MEN2B, Di Fiore went on, "is very similar to A, but, besides all ofthe above diseases, it causes more aggressive cancers, such asganglioneuromas of the gut, and skeletal deformities.
MEN2A involves a mutation in the RET receptor molecule, whichprojects through the outer surface of the tumor cell. "Thisextracellular location," Di Fiore pointed out, "offers a highlyselective target for differentiating a tumor cell from a normal one. Soyou can really think of targeting that particular residue withmonoclonal antibodies. Such simple therapy would down-regulatethe RET molecules and revert the phenotype."
His second therapeutic strategy derives from the fact that theMEN2A and B genes are dominant, not recessive. "This means." hesaid, "that if you knock out the mutant gene's protein expression,you should be able to abolish the malignant transformation signal."
Di Fiore observed, "If RET had been a recessive gene, as one mayhave supposed, you would have had to use genetic therapy to try torestore the function."
Using Reducing Agents To Reduce Consequences
His third and final therapeutic ploy "is extremely intriguing. In theMEN2A form of the disease, the mutation causes a very interestingmolecular event: it dimerizes the RET receptor." Normally, thatreceptor molecule is a monomer. In altered form, it assumes a two-subunit, dimeric, shape, consisting of two identical molecules, heldtogether by a disulfide bond.
"This bond," Di Fiore explained, "is sensitive to reducing agents, andone thing we are trying now is whether we can revert in vivo thephenotype of cells transformed by RET MEN2A by simply treatingthem with a reducing agent _ such as beta-mercaptoethanol." Headded: "We're very excited about this one; it's the main direction weare taking right now in terms of RET."
When Di Fiore said "we," he meant not only his own team at NCIbut co-authors at the University of Naples, Italy. Typical of thisongoing transatlantic collaboration, he noted, is that "the bulk of thisparticular work in Science was done by two of their scientists, whocame here to work for a while in my lab. It's a way of mergingintellects."
In citing seminal research in England and the U.S. on which his ownfinding is built, Di Fiore, quoting Isaac Newton, said, "I am a dwarfstanding on the shoulders of giants."
Molecular geneticist Webster Cavenee directs the Ludwig CancerResearch Institute in San Diego. He sits on the NCI advisory boardfor the division where Di Fiore works, and, as Cavenee toldBioWorld Today, "has watched Paolo's research develop over thepast five years."
Cavenee confirmed that "as far as I know, the RET mutation DiFiore describes is the only mutation which has been found in adominantly transforming oncogene in any human neoplasticpopulation."
He envisions "developing a pharmacologic agonist that blocks theRET activation signal. In this case," Cavenee added, "you have notonly the possibility of interfering with the transduction pathway intumors, but also of preventing the development of tumors by perhapssystemic therapy of patients who carry this inherited mutation."
Once people have found such small molecules, Cavenee concluded,"soluble, easily deliverable by mouth or injection, developed on thebasis of cell culture model systems that people such as Di Fiore havedeveloped, I would imagine they'll go into clinical trials." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.