Jordan Rethinks Hormone’s Role in Cancer

 

 

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Now at the Lombardi Comprehensive Cancer Center, celebrated researcher V. Craig Jordan is focused on finding clinical benefit in use of estrogen in women with breast cancer – a stunning role reversal for the hormone known to be responsible for cancer development in most women with the disease.

In his acclaimed battle against breast cancer, V. Craig Jordan, OBE, PhD, DSc, is pushing dogma aside once again. Whereas he gained fame in the 1970s by finding a way to shut down the ability of the estrogen hormone to fuel breast cancer growth and even initial development, he now believes that the same hormone can be given back to women as breast cancer therapy. And he is out to prove it.

Such a flip-flop view of estrogen in breast cancer may startle others, but not Jordan, the new scientific director and vice chairman of the department of oncology at the Lombardi Comprehensive Cancer Center.

That’s because this Englishman is a lover of history. “By looking back, you can see the way forward,” he says. “That is how we learn from previous generations.”

What Jordan is specifically referring to regarding estrogen is the work of Sir Alexander Haddow, a medical scientist in England who observed in the 1940s that synthetic estrogens could shrink tumors in animals. One-third of postmenopausal women with metastatic breast cancer responded to high doses of estrogen and some patients had an extraordinary regression of their cancers.

“Large tumors would just melt away, but you needed sledgehammer doses to do it – 50 times more than a woman would normally have in her body,” Jordan says.

In the 1970s, when Haddow spoke about his work, he said that to his regret, the mechanism by which these tumors melt away remained completely unknown.

That mystery is the one that Jordan and his colleagues have lately solved, and they believe the answer could possibly provide a new treatment option for women whose breast cancer has recurred and whose tumors are resistant to known antiestrogenic therapies.

But before he could reach this surprising notion, Jordan had to make his seminal discoveries, which he did starting at the University of Leeds in England. In 1969, he graduated with a degree in pharmacy and cast about for postgraduate work. His tutor suggested that he crystallize the estrogen receptor, showing it interacting with both the estrogen hormone and a synthetic anti-estrogen, which had been tested as a contraceptive in women, but which didn’t work. (In fact, the agents enhanced fertility.) “I was told I would be done in three years, but I quickly found the project challenging. Nobody could make the whole protein or make any part of it pure enough to crystallize,” he recalls.  To put the task into perspective, Jordan adds, only this year – in 2009 – has someone been able to crystallize the whole of a nuclear receptor.

So he changed his project to look at the function of the failed anti-estrogens, believing that it might be possible to use these agents as a breast cancer treatment. Scientists knew that estrogen played a role in breast cancer, but few researchers thought such an agent could be developed. “In those days, there was really no optimism about developing effective drugs to treat cancer. Chemotherapy was king and could cure cancer,” he says.  He finally collaborated with Arthur Walpole, Ph.D., a scientist at ICI Pharmaceuticals (now part of Astrazeneca) who also thought the compounds could have anticancer properties. Walpole, as Jordan’s doctoral examiner, gave the young researcher compound ICI46474 to study.

The rest is, of course, history. In 1974, Jordan showed that ICI4674 – now known as tamoxifen - could prevent breast cancer in rats by binding to the estrogen receptor. In 1978, tamoxifen was approved by the U.S. FDA for estrogen receptor positive breast cancer – the kind that most women develop.

Tamoxifen promoted a revolution in medicine. It was the first widely used endocrine therapy for all stages of breast cancer that is proven to save lives with few side effects. It was also the first drug to prevent breast cancer in well women.

In 1999, Jordan showed that another drug, raloxifene, reduced the risk of breast cancer by 76% in postmenopausal women treated for osteoporosis. Tamoxifen and raloxifene were among the first drugs known as SERMs – selective estrogen receptor modulators – that are now the pioneers for the prevention of breast cancer.

No wonder that Jordan was dubbed the “Father of Tamoxifen” by the American media. His achievements earned him countless awards, ranging from the American Cancer Society’s 2002 Medal of Honor for Basic Research to an OBE (Officer of the Most Excellent Order of the British Empire) given to him by Queen Elizabeth II. Just this year, shortly after coming to the Lombardi Comprehensive Cancer Center in order to develop what he calls a “dream team” breast cancer research effort, Jordan was elected to the National Academy of Sciences.

Now he is poised to work on a novel treatment for women who become resistant to tamoxifen or other SERMs – as many do within five years or so. “We now understand that after years of SERM therapy, tumors learn how to grow without estrogen as a fuel,” he says. “They find new pathways to grow and can even be stimulated by SERMs themselves.”

But Jordan also found “by accident and quite unpredictably,” that treating SERM-resistant cancer with low dose estrogen resulted in tumor cell death.

“Instead of supporting breast cancer growth, as it had initially, estrogen killed the cancer. No one could have guessed this and for 10 years I couldn’t get grants to further study this finding,” he says.

Jordan, however, remembered Haddow’s old experiments and he and his colleagues eventually solved the puzzle, the mechanism by which estrogen can kill breast cancer that initially needed the hormone to grow. “It’s really very clever. What we discovered is that when estrogen comes back into a cell that has stopped relying on it for growth, it looks around and says that this is not a good environment, and the hormone orders the cell to die.  We were able to show that estrogen in one context can promote cell growth but in another context, can inhibit growth by ordering programmed cell death.”

Jordan is advancing this discovery using a $10 million grant from the Department of Defense, and he directed some of those funds to collaborating researchers Anna Riegel, PhD, and Anton Wellstein, MD, PhD at the Lombardi Comprehensive Cancer Center. That successful partnership helped draw Jordan to the GUMC campus.

He now theorizes that tamoxifen is successful in part because when it stops working, the return of estrogenic activity in a woman may be keeping cancer at bay. And he believes that giving resistant women a short course of estrogen can treat recurrence – a seemingly radical notion that he wants to test in a human clinical trial.

In the future, Jordan and his team plan to map estrogen’s signaling system to find those genes and proteins that the hormone uses to tell a cell to die. Then he says it might be possible to create new drugs that work directly on those targets – thus bypassing estrogen all together.

“I want to be able to say, definitely, that I have solved Dr. Haddow’s problem – and that of many women with breast cancer or at risk of developing it,” he says.

By Renee Twombly, GUMC Communications