AWARDEE: V. Craig Jordan

FEDERAL FUNDING AGENCIES: National Institutes of Health, U.S Department of Defense

Sometimes, it’s the small moments of serendipity that define one’s path through life. So it is with V. Craig Jordan.

Jordan is known as the “father of tamoxifen,” a groundbreaking medication for breast cancer. He pioneered the scientific principles behind a new class of drugs that has helped save or improve millions of lives. And when he looks back on his accomplishments, what strikes him are the winding paths and unexpected developments that came together to produce a scientific success story.

A Winding Path to Scientific Insights

V. Craig Jordan. Photo credit: MD Anderson Cancer Center

A Texan by birth, Jordan grew up in the United Kingdom. He admits to being a lackluster student as a teenager, but he was labeled by one teacher, in a university letter of recommendation, as a “VERY unusual young man” due to his singular scholarly passion: chemistry. By that time, Jordan was independently teaching university-level biochemistry to his classmates, and he won a place at the University of Leeds in the U.K. to pursue pharmacology. As a doctoral candidate in the early 1970s, he became intrigued by the idea of using drugs to treat cancer. At the time, for cancer doctors, chemotherapy was king. Tamoxifen, unlike chemo, was not designed to kill cancer cells, so most medical professionals then thought it was unlikely to save lives. Jordan’s idea was so unorthodox, he initially struggled to find a dissertation advisor; he found one in Arthur Walpole at the chemical company ICI (which would go on to become part of AstraZeneca).

Another obstacle at the time was sexism in research. Though breast cancer can affect anyone with breast tissue, it was largely considered one of the “women’s diseases,” Jordan recalls, which were not necessarily as fashionable in pharmacology as diseases such as coronary heart disease. Despite that, Jordan became curious about antiestrogens, substances that prevent cells from making or using estrogen, a hormone critical to female sex characteristics, menstruation, and pregnancy. In 1972, with some support from the National Institutes of Health, he began a two-year stint as a visiting scientist at the Worcester Foundation for Experimental Biology in Massachusetts to study the compound ICI 46,474, a “failed morning-after pill.” While there, he conducted animal studies on the compound, studies that helped pave the way for ICI 46,474 to receive approval as the first targeted therapy for breast cancer. It is now known – particularly to breast cancer patients and their families – as tamoxifen. The failure of tamoxifen as a contraceptive was one of what Jordan would describe as a series of disappointments that would ultimately turn into scientific insights. It was at WFEB where “everything changed,” Jordan says. “There, I was allowed to put my ideas into action.”

A 1998 Chicago Tribune profile underscores the extent to which Jordan’s basic research enabled the first major clinical trial showing that tamoxifen reduced breast cancer rates by nearly half for patients at high risk: “His team’s work on lab rats has been the basis of practically every advance related to the drug, going back to his discovery in 1973 that it could treat cancer.”

Vital U.S. Funding Support

After his stint at WFEB, Jordan subsequently returned to the University of Leeds, this time as faculty. Within a few years his work was noticed by the University of Wisconsin. According to Jordan, the U.S. government’s support of scientific research was a major draw. “I have lots of stories about how my whole life has been improbable - how none of this should have happened in the first place and there should have been no science whatsoever,” he says. “It took federal funding to make this happen.”

At Wisconsin, he formed a “tamoxifen team” that carried out scientific experiments to further test the drug’s safety and effectiveness. A chance encounter with Dr. Mara Lieberman, who was studying estrogen response in animals, yielded insights into a potential new way for Jordan to test antiestrogens. Jordan hired Lieberman to his newly created team, and they collaborated to further define the way antiestrogens worked in living tissues.

Early grants were dedicated to studying the mechanisms of antiestrogen action and using animal models to predict drug effects. By the mid-1980s, tamoxifen was poised to become widely prescribed as a breast cancer therapy, but Jordan and others had concerns about potential side effects, such as bone loss or heart attacks. His lab initiated a series of experiments to test this idea.

Solving a 70-Year Mystery

In a 2019 interview, Jordan recalled, “As a pharmacologist I’m interested in mechanisms and how to explain the strange results we might get in the lab. One of these strange results came when I was at the University of Wisconsin (WI, USA), showing that tamoxifen would switch on and switch off sites around a woman’s body. In the experimental mouse model, it would cause the uterus grow, which was odd, but breast cancer would not.”

This work led to a body of knowledge around a new class of drugs called selective estrogen receptor modulators, or SERMs. What was so strange about SERMs – and so unpredictable – was the fact that they affected certain tissues differently than others. In 1990, Jordan published his vision of the new group of medicines. Later, he gave a talk entitled “The World Turned Upside Down,” a nod to the unanticipated victory of U.S. revolutionaries at the Battle of Yorktown, in reference to the surprising finding that estrogen inhibited, rather than stimulated, the growth of certain breast cancer cells.

In some tissues, SERMs behaved like estrogen. But in others, they blocked its action. This was confounding. Estrogen is an important hormone, yet contradictory; as Jordan explains, it can be both helpful and harmful. It is necessary for reproduction and also helps maintain body temperature, safeguard the heart from the buildup of plaque in coronary arteries, preserve bone density, and strengthen vaginal health. However, it can also promote breast and uterine cancer.

Thus, the conventional wisdom at the time was that estrogen would prevent osteoporosis and heart disease – which led to the reasonable assumption that using an antiestrogen to treat breast cancer would promote these conditions in patients. Surprisingly, this turned out to not be true, and Jordan’s studies showed it. Though estrogen can fuel breast cancer growth, it can also kill vulnerable breast cancer cells under the right conditions. In figuring out how estrogen can both promote and prevent breast cancer, Jordan and his colleagues “solved a 70-year mystery.”

Unraveling SERMs’ Secrets

Tamoxifen is perhaps the best-known SERM; many breast cancer patients rely on the drug for its estrogen-blocking properties. As with most targeted drugs, however, the long-term problem with tamoxifen is acquired resistance. Jordan and his teams devoted themselves to unraveling the mechanism and timeframe for this to occur in patients. Among the important principles the team learned – in particular, through the experiments of Marco Gottardis, then one of Jordan’s trainees – is that while tamoxifen blocks breast cancer growth, it also stimulates endometrial cancer growth in animals. This ultimately led to a change in clinical care and enhanced patient safety. Other colleagues who made key experiments in his labs at multiple institutions included Anna Riegel, Doug Wolf, S.Y. Jiang, Mei-Huey Jeng, Bill Catherino, Anait Levenson, Joan Lewis, Eric Ariazi, Ping Fan, Philipp Maximov, and Balkees Abderrahman.

Said Jordan in a video produced by his current institution, The University of Texas MD Anderson Cancer Center, “We needed to find out everything we could about tamoxifen.” Tamoxifen is now on the World Health Organization’s list of essential medicines. “We worked out exactly the strategy to use to target only those tumors that have estrogen receptors,” he added. “It was the first targeted therapy.”

With the critical contributions of the Jordan lab experiments, scientists conducted a large-scale study published in 1998 demonstrating that tamoxifen can prevent breast cancer in women as young as 35 who are at high risk. No drug had ever before been shown to help stave off breast tumors like this.

There were more scientific mysteries to solve. The Jordan lab was integral to the development of the SERM raloxifene to prevent and treat the bone disorder osteoporosis, which makes bones weaker and increases the chance of fractures. But when the lab tried to publish some of the experiments, osteoporosis journals initially rejected the findings, saying that since estrogen preserved bone loss, it didn’t make sense that antiestrogens would do the same thing.

Raloxifene has also proven effective in the prevention of breast cancer without raising the risk of endometrial cancer after scientists tested it in post-menopausal women who, aside from their age, had no other apparent risk factors. A large-scale clinical trial called the Study of Tamoxifen and Raloxifene (STAR) demonstrated that both compounds showed a decrease in breast cancer in high-risk women, and raloxifene produced fewer adverse effects.

A Maverick in Science

A letter from Princess Diana to Dr. Jordan. “I wish you all the strength to press ahead with your vital work.”

Jordan’s work through the years to unravel the secrets of SERMs has been funded by NIH and the Department of Defense, with additional support from philanthropic organizations. He has published hundreds of peer reviewed papers on antiestrogens, as well as contributed to many books and conferences and served on several editorial boards. His work has resulted in multiple scientific awards. Perhaps the most exciting was an appointment by Queen Elizabeth II as a “Companion of the Most Distinguished Order of St. Michael and St. George” for services to women’s health. Jordan also befriended another royal, Princess Diana, after he was tasked with organizing a conference in Chicago in her honor. He subsequently became Northwestern University’s first endowed chair named after the princess in the wake of her tragic death.

“Sometimes you need mavericks in science that don’t follow what everyone else does,” says Gottardis, now at the Janssen Pharmaceutical Companies of Johnson & Johnson. “[Jordan] was lucky to get funded by NIH; otherwise, this wouldn’t have happened. Somebody believed in him.”

In 2014, Jordan went full circle: He returned to Texas, the state of his birth, to join MD Anderson. Though he built a decades-long career in the United States, Jordan maintained another connection with the country in which he spent his childhood, the United Kingdom. According to an MD Anderson profile, “For the past 50 years, Jordan has led what he calls a ‘double life.’ For his day job, Jordan developed breakthrough breast cancer treatments, pioneering the estrogen-blocking drug tamoxifen, which has been credited with saving the lives of millions of women worldwide. But for most of his career, Jordan also served as a reserve officer in the British Special Air Service (SAS), one of the most elite military units in the world. Founded in 1941, the SAS is the rough equivalent of the U.S. Army Green Berets or Navy SEALs — a small, secretive fraternity of Special Forces soldiers and intelligence officers.”

In 1990, when Jordan wrote his first paper on SERMs, the new class of drugs was an idea. Now five of them have been approved by the Food and Drug Administration, and millions of lives have been saved or improved – which shows that little moments of serendipity can add up to make a big difference.

Dr. Jordan receiving an award from Prince William, The Duke of Cambridge

By Erin Heath