When a mouse comes down with ovarian cancer, it dies in a matter ofmonths. Of the 24,000 women diagnosed last year with this lethalmalignancy, only 17 percent will survive more than five years. Thesegrim statistics have not changed in 30 years.
In about one-third of all ovarian tumors, the smoking gun is anoncogene called HER-2/neu. All patients with five or more copies ofthis oncogene in their tumor cells will be dead within two years.
To stop that smoking gun from shooting is the job of an oncogene-repressing gene called E1A.
To bring that E1A to its HER-2/neu target, RGene Therapeutics Inc.,of The Woodlands, Texas, couples the E1A DNA to a liposomalvector it calls DC-Cholesterol. (See BioWorld Today, Dec. 15, l994,p. 1.)
On Friday, the tumor biologist who discovered E1A's repressorfunction, Mien-Chie Hung, is presenting a poster at a KeystoneSymposium on "Gene therapy and molecular medicine" in SteamboatSprings, Colo. He will report how the gene has kept mice infectedwith human ovarian cancer alive and in remission, far beyond thenormal life expectancy for the disease.
Hung, a scientific co-founder of RGene, teaches virology at theUniversity of Texas M.D. Anderson Cancer Center in Houston. Heinjected highly active human ovarian cancer cells into the peritonealcavity of 20 nude mice. This mimicked the advanced Stage III of themalignancy in women, after their cancer spreads from its primarybase in the ovaries into the abdomen.
Five days after this seeding of the cancer cells, clusters of adenomacells, over-expressing the oncogene, had developed in the peritonealcavity. At that point, Hung began weekly injections into the cavity ofE1A repressor genes, complexed to cholesterol-based liposomevectors. There they quickly attached to the tumor cells, but lefthealthy ones alone.
This avoidance of possible side-effects, Hung told BioWorld Today,"results because E1A has only transient expression of its geneproduct. To remain active, it must be injected repeatedly."
To date, he said, "about 70 percent of those mice have survived formore than one and one half years, free of tumor." This despite thefact that he stopped their once-a-week E1A gene therapy after eightmonths.
But 100 percent of control mice developed severe tumor symptoms,and all were dead by 160 days.
Hung explained that E1A represses HER-2/neu "because it is a post-translational factor that inhibits the oncogene's promoter, so it cannotmake RNA from DNA." Hung discovered E1A in a non-pathogenicstrain of adenovirus, which is remotely related to common-coldviruses.
Besides showing the efficacy of RGene's E1A-cholesterol vector,Hung compared it experimentally to current efforts at ovarian cancergene therapy, using replication-deficient adenoviruses as E1Avectors.
He injected ovarian-tumor-bearing mice with that viral constructrepeatedly for 4.5 months. At 10 months, 80 percent of the murinerecipients were still alive, whereas all controls had died by 4.5months.
Hung observed that the viral delivery system has encountered"serious immune-response difficulties."
RGene's president and CEO, Martin Lindenberg, regards thiscomparative trial as the high-point of Hung's presentation. "It'scritical information," he told BioWorld Today, "that shows theequivalence between the adenoviral and non-viral vector systems, sonow we can go ahead." He expects human clinical trials to begin"before the end of 1995." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.