diets, 50% of the mice fed CDDO-Me and 43% of the mice fed the rexinoid had developed tumors. But still hardly any tumors were found in the mice fed both drugs.
Liby followed a similar protocol in two other studies, looking at the prevention of lung tumors; both of them used CDDO-Me, other CDDO derivatives, and the same rexinoid. All of the compounds dramatically reduced the number and size of lung tumors, too. Liby and Sporn hope to publish the results of all three trials soon.
Given the lack of apparent side effects and the spectacular efficacy that the rexinoid demonstrated in Liby's studies, one might expect the maker of that drug to be very interested in collaborating with Sporn's lab and Reata. But it's not, according to Sporn. Ligand Pharmaceuticals had been developing the rexinoid, officially named LG100268, for a purpose other than cancer treatment and prevention. However, Ligand seems now to have abandoned the development of LG100268. It's not listed in the "product pipeline" on the Ligand website, and a company spokesperson declined to comment on it further.
Sporn first published data on LG100268 in the October 2002 issue of Clinical Cancer Research. He and his postdoc at the time, Nanjoo Suh, demonstrated that when used in combination with a drug called Arzoxifene, which was being developed by Eli Lilly, it was extremely effective at reducing the size and number of estrogen-receptor-positive (ER+) breast tumors. Four years later, in the October 2006 issue of the same journal, Sporn and Liby demonstrated that Arzoxifene and LG100268, when used in combination, completely suppressed the formation of ER- tumors in mice. All of the mice fed the control diet developed tumors, while none of the mice fed the combo diet did.
This should have been big news because, as Liby and her coauthors noted, no drugs exist to prevent ER- breast cancer in women. (In contrast, tamoxifen and raloxifene are effective for ER+ breast cancer.) Yet the findings were met with silence. "We're rather depressed that nothing has happened with this in the real world," Sporn told the scientists who attended his AACR talk.
"I've agitated with Eli Lilly," Sporn says. "I've agitated with Ligand." He's also tried to get the National Cancer Institute and breast cancer advocacy groups to promote the development of Arzoxifene and LG100268, he says. But a collaboration between two companies "involves getting their lawyers together to share intellectual property," he notes, "which they do not want to do."
Dr. Powel Brown, a professor at Baylor College of Medicine and another of the presenters at the AACR conference, has also found LG100268 to be highly effective at preventing ER- breast cancer in mice. "It's extremely frustrating to have an agent that is so active and so nontoxic, at least in mice, and to not be able to develop it."
For now, the best hope for new chemoprevention agents seems to lie with triterpenoids. Huff acknowledges the tremendous financial and litigation risks that pharmaceutical companies face when investing in cancer prevention drugs. But for Reata, the hurdles with triterpenoids are a little lower, he thinks. If a drug can be used only for prevention, then it's very difficult for a
Liby followed a similar protocol in two other studies, looking at the prevention of lung tumors; both of them used CDDO-Me, other CDDO derivatives, and the same rexinoid. All of the compounds dramatically reduced the number and size of lung tumors, too.
company to justify investing in it, he says. But because the triterpenoids are so potent and have such a broad range of activity, they can be used for much more than just prevention.
"This isn't a question of whether the drugs should be tried for prevention or not," Huff says. "They should be tried for prevention," as well as for several other inflammatory-related diseases. But first Reata will get the drugs approved for treatment of late-stage cancer—a less risky prospect—and then work toward prevention trials.
Huff is optimistic, as are Liby, Gribble, and Honda. All of them have high hopes for the