Translating Basic Research into Patient Care: An Interview with Dr. Angela Brodie

Researchers at the University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC) are dedicated to conducting basic scientific research to discover new and better ways of preventing and treating cancer. Angela Brodie, PhD, professor of pharmacology and experimental therapeutics at the University of Maryland School of Medicine, and a researcher at the UMGCCC, pioneered the development of a new class of drugs known as aromatase inhibitors, which are now widely used to treat and prevent breast cancer. Here Dr. Brodie discusses her research and the dynamic relationship between clinical practice and laboratory discoveries.

You discovered aromatase inhibitors about 10 years ago, and now they are becoming the new standard of care for postmenopausal women with hormone sensitive breast cancer. What originally led to your discovery?

My research interest is the biochemistry of what makes cells change to become cancer. We already knew that many breast cancers are hormone-dependent — meaning that estrogen stimulates their growth by "turning on" estrogen receptors in the cancer cells. Without estrogen, the cancer cells are not stimulated to grow and they don’t reproduce.

I was interested in looking at the biochemistry of how estrogen is synthesized in the body and trying to develop compounds that would inhibit estrogen synthesis and thereby control tumor growth.

The standard treatment for breast cancer at the time was tamoxifen, which is an anti-estrogen. It deprives cancer cells of the growth effects of estrogen by blocking its binding to the estrogen receptor. However, it was also known that tamoxifen itself is a weak estrogen, as well as an estrogen antagonist. This means that there is always a slight estrogenic effect and as a result, tumors are not always suppressed. Tamoxifen is effective for about five years, but if patients were kept on it longer, there was no further benefit. Tamoxifen has also some negative side effects, like increased risk of stroke and endometrial cancer.

I thought that it might be useful to take a totally different approach to the problem by inhibiting the synthesis of estrogen, rather than blocking its action once it was already made in the body. We developed compounds and found that they successfully inhibited the synthesis of aromatase in animal models.

These compounds, known as aromatase inhibitors, lower the amount of estrogen made in the body after menopause. Without estrogen the growth of cancer slows or stops Three of these compounds are now FDA approved for use in women with estrogen receptor positive metastatic breast cancer.

How does it feel to have discovered a major new type of drug that is actually on the market and being used to help patients?

Bringing a new discovery from the laboratory into the clinic is a long, involved process. Initially, doctors were reluctant to try an experimental drug when tamoxifen was already working in their patients. Our animal models clearly showed that aromatase inhibitors worked well. We experimented with animal models to test combinations of tamoxifen and aromatase inhibitors. But the results showed that this wasn’t an improvement, and the subjects were better off on only the aromatase inhibitors. And that is exactly what subsequent clinical trials proved later on.

It’s very gratifying to know that something you developed is actually helping patients with cancer. In the beginning, the scientific community was convinced that this new approach wouldn’t work, that anti-estrogens were the only way to go. We tried to interest a number of drug companies in manufacturing these new compounds, but new drug development is a risky business and they were not terribly interested. It wasn’t until my colleagues in London began conducting clinical trials with our compound formestane and showing positive results that we were able to interest the pharmaceutical companies in developing this class of drugs.

Formestane was the first selective aromatase inhibitor to be used clinically, and at that time was the only new drug specifically designed for the treatment of breast cancer in 10 years. It was released for worldwide use in 1994. More recently, in 2003 letrozole was found to be so effective in early breast cancer after five years of tamoxifen that a recent clinical trial was stopped early so that patients who had been taking the placebo could be given the new drug.

In one Canadian-led trial, aromatase inhibitors were found to reduce death from breast cancer by up to 40% in postmenopausal patients. Is there any applicability for premenopausal women?

So far, we’ve focused our research on postmenopausal women because this is the larger group of patients and are the ones who have the most estrogen receptor positive tumors. In order to benefit from hormone therapy, the patient’s tumor must be estrogen sensitive, and most breast cancers in premenopausal women are not. They tend to be more difficult cancers to treat. Also, it is not known what the long-term effects would be of suppressing estrogen production over long periods of time in younger women.

What new research is currently underway to treat or prevent the spread of breast cancer?

We have recently joined with our colleagues at Johns Hopkins and at the University of Texas M.D. Anderson Cancer Center in a new $10 million grant from the U.S. Department of Defense. We’ll try to identify genes that aid the spread of the cancer and then develop novel therapies to target them. This is an extremely important area of study, one that may well hold the key to finding new approaches for treating breast cancer.

Our team will focus on designing new therapies using molecular modeling and high throughput screening technology to identify promising new compounds that interact with molecules discovered by our fellow researchers at Hopkins and M.D. Anderson.

Recently, the breast cancer research and prostate cancer research programs at UMGCCC have merged into one program called Hormone Responsive Cancers research program. What was the reason for this programmatic change?

There is quite a bit of overlap in our efforts to identify molecules that inhibit tumor growth. Both breast cancer and prostate cancers are affected by hormones produced within the body. By merging our research programs, we can collaborate and take advantage of the basic science discoveries that have application in all hormone responsive tumors.

We did some research looking at the effect of estrogens on the prostate, but we believe that androgens has a much more important role in prostate cancer. So, we are now working on developing inhibitors of androgen synthesis. We have identified a few compounds that look promising that we are currently testing in animal models.

A major problem with all tumors is that they can devise ways to survive the treatment that patients receive. They can adapt and grow even during the therapy. Our strength is in new drug development for cancers, targeting those elements that cause or stimulate the growth of tumors. These studies could help us understand the mechanisms involved in drug resistance and lead to new ways to improve treatment and prevention of cancer.