More Selective Antiestrogens Under Development

ABSTRACT: An expert panel of 10 international cancer researchers and practicingoncologists met in Boston to discuss the past, present, and future usesof antiestrogens in the treatment of breast cancer. The first five articlesin this series, based on the symposium presentations, appeared in OncologyNews International in Oct 1996 , Nov 1996 , Dec 1996 , Jan 1997 , and March1997 ). This article on new endocrine therapies is the last in the series.The symposium was sponsored by Zeneca Pharmaceuticals.

BOSTON--New endocrine therapies are being developed for use in advancedbreast cancer, as adjuvant therapy, and possibly for prevention, but theyare unlikely to gain acceptance unless they have some clear advantage overtamoxifen (Nolvadex). Anthony Howell, MD, of the Christie CRC ResearchCentre, Christie Hospital NHS Trust, Manchester, England, described sixnew nonsteroidal antiestrogens in various stages of development and onesteroidal agent.

"Most of these nonsteroidal drugs are based on the triphenylethylenestructure of tamoxifen, except for raloxifene, which is a benzothiaphene,"he said. These molecules were chemically altered to try to improve upontamoxi-fen's effects, in terms of increased anticancer activity, decreasedside effects, or increased effects on overall health (reductions in cardiovascularand skeletal events).

Dr. Howell noted that toremifene (Fareston) has been approved in manycountries and appears to be close to approval in the United States. "Butif you look at the preclinical and clinical data, you can't see any advantageto this drug over tamoxifen," he said, citing a head-to-head randomizedtrial in advanced breast cancer in which the two drugs gave the same results.

Droloxifene, which binds more avidly to the estrogen receptor than tamoxifen,is currently in phase II clinical trials in Canada. Preclinically, in theimmature rat uterus assay, it had more antagonist activity than tamoxifenand reduced agonist activity.

He cited two possible advantages of droloxifene: It appears to havesome cross-sensitivity with tamoxifen and thus may be active after tamoxifenfailure, and it has a short half-life and thus might be useful in alternatingschedules with other drugs.

There is much interest in raloxifene, he said, because it seems to bequite active on bone but not on the uterus, and thus may be useful in preventingosteoporosis. "To date, it does not look like a very active drug interms of anticancer activity, but we await further data on that,"he said.

Preclinical testing of TAT-59 from Japan and idoxifene from the RoyalMarsden Hospital suggests that both may have a better profile than tamoxifen,"but they're in phase II trials at the moment," he said, "andwe won't know for some time whether they are more active."

As far as side effects are concerned, most of the newer compounds lookvery similar. Said Dr. Howell: "In terms of long-term effects on thecardiovascular systems and on bone, we don't have any data to indicatethat any of these are better than tamoxifen."

When Wakeling and Bowler were asked to develop a new antiestrogen, theybypassed the tamoxifen molecule, Dr. Howell said. These researchers wentback to the estradiol molecule and added a long side chain on the 7 alphaposition, to produce a so-called pure antiestrogen that has little or noagonist activity.

In immature rat uterus assays, the first such compound, ICI 187,780completely inhibited rat uterine growth in the presence of estrogen andshowed no antagonist activity in the absence of estrogen, "and thisis the first glimmer of a possibly better antiestrogen coming from thelaboratory," Dr. Howell said.

One dose of a similar compound, ICI 182,780, lowered estrogen-receptorpositivity in biopsy specimens of women taken before and after antiestrogentreatment, whereas tamoxifen does not seem to have this effect.

Long Duration of Response

In a recently published clinical trial, ICI 182,780 was given to womenwho had relapsed on adjuvant tamoxifen or who had received tamoxifen atrelapse and then progressed. Nineteen of these patients remain in remissionafter 36 months. The median duration of response has been about 25 months.Dr. Howell said that preclinical studies of the compound in nude mice predicteda long duration of response.

"The question is, Why should this drug be possibly better thantamoxifen?" he asked. Tamoxifen inhibits trans-activating function2 (TAF2) in the ER protein, but does not inhibit TAF1, and this may bethe reason for its partial agonist activity, he explained. ICI 182,780,on the other hand, seems to inhibit both TAF1 and TAF2, thus potentiallycausing a greater shut off of transcriptional activity in estrogen-stimulatedgenes.

Dr. Howell briefly mentioned that a whole series of so-called transcriptionalintermediate factors (TIFs) are currently being characterized. These TIFsmust be activated for gene transcription to take place.

"So I can see a tremendous future in selectively inhibiting theseTIFs in different ways to make endocrine therapy more precise," hesaid. "Someday, after many of us have retired, the golden age of endocrinetherapy might actually arise."