Jordan Proves Discovery Has No Limits

If you tell Craig Jordan, PhD, OBE, DSc, that something won't work, you can bet he might try it anyhow. And if history serves as precedent, he'll find a way to make it work. That's exactly what he did three decades ago when he took a failed contraceptive and transformed it into the number one breast cancer treatment and prevention drug ever made. We know it as tamoxifen.

Adversity didn't stop him later when he found that although another drug, raloxifene, failed to treat breast cancer, it was very effective in treating osteoporosis and actually preventing breast cancer in post-menopausal women.

Raloxifene is poised to receive FDA approval for the prevention of breast cancer as a result of its effectiveness in the Study on Tamoxifen and Raloxifene (STAR trial), a large international effort of clinicians, scientists and volunteer patients.

Mary B. Daly, MD, PhD, FACP, senior vice president for population science and director of the Margaret Dyson Family Risk Assessment Program, was the lead investigator for the study at Fox Chase. Jordan, vice president and scientific director for medical science at Fox Chase Cancer Center, served as the scientific chair for the oversight body, the National Surgical Adjuvant Breast and Bowel Project.

"What is remarkable is that the discoveries [of tamoxifen and raloxifene] were born in the same laboratory," says Jordan.

Jordan has spent his career studying the effects of drugs like tamoxifen and raloxifene on breast tissue. Called selective estrogen-receptor modulators (SERMs), these drugs selectively inhibit or promote estrogen-like growth in different tissues. For example, while a SERM may block estrogen in the breast, it could be estrogen-like to improve bone density.

Approximately 80 percent of breast cancers are driven by estrogen-controlled cell proliferation. When anti-estrogens, like tamoxifen, attach to estrogen receptors on/in the breast cancer cell, they prevent cell growth by blocking the binding between estrogen and the receptor.

For many years, tamoxifen has been the gold standard of follow-up treatment for patients with estrogen-receptor positive cancers. It also is used as a preventive agent for high-risk women. Side effects such as blood clots and endometrial cancer are a concern for postmenopausal women taking tamoxifen; these are less common for premenopausal women. With the approval of raloxifene, postmenopausal women will have another option. Raloxifene is not recommended for use in pre-menopausal women because studies in this age group have not yet been completed.

"Raloxifene is equivalent to tamoxifen for postmenopausal women for the prevention of breast cancer," says Jordan. "It blocks the production of estrogen-receptor positive cancer with less concern for side effects."

None of this comes as a surprise to Jordan, a pharmacologist at heart, who has a knack for spotting disregarded drugs and finding their strengths.

His current project investigates resistance that breast cancers develop in response to tamoxifen and other long-term anti-estrogen therapies. He has received a $10.7 million Breast Cancer Center of Excellence grant from the Department of Defense to study a serendipitous finding. His lab has discovered that reintroducing small amounts of estrogen to treat breast cancer cells, following a woman's development of drug resistance, now actually initiates rapid cancer cell death.

"We need to marshal this knowledge to help patients," Jordan says. "Estrogen either turns on or turns off certain switches and we need to find out how estrogen receptors find those switches. Maybe all cancers are like that. We need to find out."