Jordan began working on the structure-activity of anti-estrogens as part of his PhD program at Leeds University. During that time, he met Arthur Walpole, the patent holder for the drug that became tamoxifen. In September 1972, Jordan became a Visiting Scientist at the Worcester Foundation for Experimental Biology, Massachusetts. While there he began researching the idea that tamoxifen, a selective estrogen receptor modulator (SERM), could block estrogen receptors in breast tumors. Estrogen receptors in breast tumors attract estrogen which is then absorbed into the cancerous cell and encourages the cell to divide, causing the cancer to grow. Until this time, the treatment for this type of breast cancer was oophorectomy. Jordan returned to Leeds University as a Lecturer in Pharmacology between 1974 and 1979, after which he spent one year at Ludwig Institute for Cancer Research at the University of Bern, Switzerland. In 1980, Jordan joined the University of Wisconsin–Madison where he started to look at the effects of tamoxifen and another SERM, raloxifene, on bone density and coronary systems. This was needed because of the concern that long term use of SERMs could lead to osteoporosis and heart disease. Jordan’s research showed that post-menopausal women who took these drugs did not suffer from a lowering of bone density or an increase in blood cholesterol. Raloxifene is now used in the prevention of osteoporosis. Jordan gained a full Professorship at Wisconsin in 1985, the same year his alma mater awarded him a DSc. In 1993, Jordan became Professor of Cancer Pharmacology at Northwestern University Medical School in Chicago, IL., and director of the Breast Cancer Research Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. He was the inaugural holder of the Diana Princess of Wales Professor of Cancer Research (1999–2004).
In January 2005, Jordan was the inaugural Alfred G. Knudson Chair of Cancer Research at the Fox Chase Cancer Center in Philadelphia, PA. He has recently published work showing that estrogen, given at the right time, causes the destruction of cancer cells rather than feeding their growth. Jordan was the Scientific Director of the Lombardi Comprehensive Cancer Center, Professor of Oncology and Pharmacology, Vice Chair of the Department of Oncology, and the Vincent T. Lombardi Chair of Translational Cancer Research, Georgetown University, Washington, D.C., prior to moving to Texas MD Anderson Cancer Center.
His first lecture will be presented on Thursday April 30th 2015 and is titled:
Drug Resistance to Antihormone Therapy: Estrogen Induced Apoptosis
High dose estrogen therapy for the treatment of post-menopausal women with breast cancer was the first treatment shown in clinical trial to rationally treat any cancer. This was the standard of care for post- menopausal patients for 30 years before the introduction of tamoxifen in the 1970’s. An understanding of how estrogen can be used as an anti-cancer agent has now been deciphered in the laboratory over the past 15 years. Rules have now been established to understand why long term estrogen deprivation can cause selection of new population of estrogen receptor positive breast cancer cells that can survive without estrogen but are now vulnerable to estrogen induced cell killing. The story of understanding estrogen induced apoptosis in the laboratory is consistent with clinical observations. In the laboratory, estrogen induced apoptosis is a prolonged process completely unlike cell killing with cytotoxic chemotherapy. The estrogen receptor is the dominant signal transduction pathway in estrogen induced apoptosis, and the events to cause apoptosis are triggered by the shape of the estrogen receptor complex. This slows down apoptosis from hours into days. Estrogen induced apoptosis produces an inflammatory response in the estrogen deprived breast cancer cell. This inflammatory response can be blocked by steroidal glucocorticoids. This discovery by Jordan’s laboratory opened the door to understanding why the estrogen only trial of the Women’s Health Initiative caused a decrease in breast cancer, but the trial using a combination of estrogen medroxyprogesterone acetate (MPA) caused an increase in breast cancer. Jordan discovered that the glucocorticoid like properties ofMPA stopped estrogen induced apoptosis in the estrogen deprived cells. This research now opens the door to the opportunity of developing of hormone replacement therapies for women that contain not only estrogen, but also a synthetic progestin that will protect the women’s uterus from the effects of continuous estrogen therapy, thereby lowering the risk of endometrial cancer, but have estrogen-like actions to reinforce estrogen killing breast cancer cells.
His second lecture will be presented on Friday May 1st 2015 and is titled:
The Tamoxifen Tale and Beyond
In 1970, the pharmaceutical industry was not interested in developing drugs to treat cancer. In 1970, there was no tamoxifen, raloxifene , or selective estrogen receptor modulators (SERMs). All hopes on the cure for cancer were pinned on combination cytotoxic chemotherapy, because this approach had been remarkably successful for curing childhood leukemia and Hodgkin’s disease. The pharmaceutical industry at the time had been particularly interested in developing new forms of contraception hot on the heels ofthe enormous success of the oral contraceptive introduced in 1960. However, the group of chemicals called non-steroidal anti-estrogens were found to be perfect “morning after pills” in rats, but did exactly the opposite in women by inducing ovulation. In 1970, Jordan was conducting his PhD research on these failed morning after pills, but by a series of lucky coincidences, he turned his attention to a compound called ICI 46, 474, which became tamoxifen. Jordan reinvented the strategy of using tamoxifen to treat and prevent breast cancer, and as a result, changed medical practice by introducing the first targeted therapy for cancer shown to save lives. From this work in the 1970’s, Jordan studied the pharmacology of non-steroidal anti-estrogens and by 1980, he had discovered that these compounds switched on or switched off estrogen target tissues around the body. Tamoxifen maintained bone density, decreased circulating cholesterol, but at the same time, blocked estrogen stimulated breast cancer growth. He also discovered that tamoxifen had the potential to increase the risk of endometrial cancer. He conceived the idea that became today the new group of medicines called SERMs. Raloxifene was the result, a medicine that is FDA approved to treat and prevent osteoporosis, but prevents breast cancer at the same time. It does not increase the risk of endometrial cancer. Today, there are 5 FDA approved SERMs: tamoxifen, raloxifene, toremifene, bazedoxifene ,and ospemifene. Millions of women around the world continue to gain benefit either by increased survivorship from breast cancer, or by improved quality of life, reducing the risk of breast cancer, or improving post-menopausal quality of life.