A Bench-to-Bedside Story
“WE’RE ALWAYS LOOKING FOR STORIES where what we do at the bench impacts what we do in the clinic,” says Donald McDonnell, PhD, coleader of the Women’s Cancer Research Program at Duke Cancer Institute. “Like one where a young graduate student finds a drug, then the drug is patented, licensed, and in a phase two trial within a matter of a couple years. You can count on one hand the number of times that happens.”
This was one of those times.
Once Upon a Time in a Lab Far, Far Away
Four years ago, Kaitlyn Andreano, then a PhD student in the Department of Pharmacology and Cancer Biology training in McDonnell’s lab, uncovered a novel use for an old osteoporosis drug called lasofoxifene—as a possible treatment for metastatic breast cancer.
Lasofoxifene, a type of endocrine or hormonal therapy, is a selective estrogen receptor modulator (SERM). In breast cancer, SERMs work by sitting in the estrogen receptors in breast cells, thus blocking the effects of estrogen in the breast tissue. However, paradoxically, they also function as estrogens in bone and protect against osteoporosis.
Lasofoxifene was first discovered in 1992 through a research collaboration between California-based Ligand Pharmaceuticals and Pfizer Inc. McDonnell, a young researcher with Ligand at the time, was part of the team developing the drug to treat osteoporosis in women as a result of estrogen loss in menopause.
“Estrogens are generally very protective against bone loss, but people don’t like the side effects of those drugs,” says McDonnell.
“When I was a young guy with dark hair, I figured out how to manipulate the estrogen receptor to identify drugs that inhibited the negative actions of estrogen in breast cancer cells, but which were bone protective. Building on this discovery, and upon arriving at Duke in 1994, I set out to identify ER (estrogen receptor)-targeting drugs that worked better than those available and that would be particularly effective in the treatment of metastatic breast cancer.”
Seventy to 80 percent of the more than 270,000 invasive breast cancers diagnosed annually in women in the United States, are estrogen receptor-positive (ER+). Endocrine therapies are standard of care for these patients. This includes SERMS (drugs in the same class as lasofoxifene) and selective estrogen receptor degraders (SERDs)—both of which target the estrogen receptor present in cancer cells and in the body’s immune cells—and aromatase inhibitors, which suppress estrogen synthesis.
More than 1.5 million women in the U.S. are currently on endocrine therapies for breast cancer—either as monotherapies or in combination with other drugs. These drugs and drug combinations have been found to work well, in some cases for many years, until they don’t.
Cancer is smart. Mutations can develop in breast cancer cells that render the best therapeutic strategies ineffective. While more and more women are living with stage 4 breast cancer (upward of 150,000), 42,000 die of metastatic breast cancer each year. Metastasis, cancer that has spread to distant organs, is the major cause of breast cancer death.
A few years ago, McDonnell explains, it became apparent to researchers across the world that estrogen receptor mutations that developed in breast cancer cells as the cancer spread—ESR1 mutations— were one cause of this acquired resistance to endocrine therapy and a likely driver of that breast cancer spread. Upon close inspection, it was discovered that between 30 to 40% of patients with ER+ breast cancer, especially those who’d been extensively pretreated with aromatase inhibitors, would go on to develop an ESR1 mutation.
In early 2016, a Duke physician-scientist who’d completed her doctoral training in McDonnell’s lab—Stephanie Gaillard, MD, PhD—had come across an ESR1 mutation in an ovarian cancer. Gaillard shared this with the lab, believing McDonnell might have some ideas as to how to leverage this information to help patients whose cancers harbored these mutations.
That’s when Kaitlyn Andreano, the graduate student in McDonnell’s lab, took on the project.
“Kaitlyn decided to collect or synthesize nearly every endocrine drug that had ever been made, which is easy enough to do in my lab because we've been involved in the development of most of them, and she screened and found that lasofoxifene alone was effective against pretty much all of the ESR1 mutations, it didn't seem to care,” says McDonnell. “We knew that if you developed an ESR1 mutation, you would be resistant to all the endocrine therapies we have, but lasofoxifene was different.”
Predicting that lasofoxifene would work in ER+ breast cancer, the lab filed what’s called “an invention disclosure” on May 25, 2016.
Next, Andreano pushed for a utility patent. Without this, she and McDonnell assessed, the “old drug” would never be developed. Because the discovery was made in a Duke lab, Duke University filed, in October 2017, a utility patent for the use of lasofoxifene to treat ER+ breast cancer. The patent was issued in April 2019 with Andreano, Ching-Yi Chang, PhD, MSPH (research associate professor of pharmacology and cancer biology), Gaillard, and McDonnell listed as inventors. Lasofoxifene looked promising— where other endocrine therapies had failed—for the treatment of metastatic breast cancer in patients with the ESR1 mutation. Next, to translate these findings in the lab to clinical use.
The owner of the U.S. rights to lasofoxifene at the time was Ohio-based Sermonix Pharmaceuticals. The company’s CEO, David Portman, MD, had acquired the rights to the drug in February 2015, just a couple months after he and his wife Miriam Davidson Portman, MD, founded the company.
Portman—an OB-GYN by training and clinical researcher in women’s health, sexual medicine and menopause—had been principal investigator for Pfizer during some of their phase two and phase three studies of lasofoxifene in osteoporosis. He’d also consulted on the drug’s gynecological effects, including the alleviation of vaginal dryness/atrophy in menopause that can cause painful intercourse and sexual dysfunction.
“This particular compound was looking for a good home,” says Portman. “We were fully prepared to try to move it forward in what had already been studied in menopause and osteoporosis, to pick up where Pfizer left off.” But then they came across the invention disclosure filed by the McDonnell lab. “This seemed to be a much more important area of unmet medical need. We had no idea, when we started, that we’d end up in the metastatic breast cancer space.”
On November 8, 2016, even before a patent was issued, Sermonix and Duke’s Office of Licensing and Ventures came to an agreement whereby the company would acquire exclusive rights to further develop what was Duke’s intellectual property. If the Food and Drug Administration (FDA) approved the drug, Sermonix would commercialize lasofoxifene to treat advanced and metastatic breast cancer.
Sermonix also expanded its agreement with Ligand from U.S. rights to worldwide licensing rights, clearing the way for a launch of an international multi-site clinical trial “Evaluating LAsofoxIfeNe in ESR 1 Mutations,” the ELAINE Study, named for Portman’s sister-in-law Elaine Davidson Nemzer, MD, a child psychiatrist who passed away from metastatic breast cancer 20 years previous at the age of 47.
The ELAINE Study enrolling its first patient in September 2019 at the Mayo Clinic in Rochester,
Minnesota—as a phase two open-label study with Fast Track designation by the FDA. (There was no need for a phase one trial since dosing and safety were already evaluated in the studies of lasofoxifene for osteoporosis.)
The trial compares lasofoxifene to fulvestrant, a current treatment for metastatic breast cancer, in postmenopausal women and premenopausal women with locally advanced or metastatic ER-positive breast cancer and an ESR1 mutation whose disease has progressed despite treatment with the standard-of-care therapy.
Duke Cancer Institute opened a study site in September 2020 and enrolled its first patient on November 9, 2020, with DCI medical oncologist Sarah Sammons, MD, as the clinical principal investigator.
The company’s goal, Portman said, is to fully enroll the study (100 patients) by early 2021 and have phase two results data to report by early 2022.
Every patient at the trial sites who meets the criteria will have the chance to be screened for the trial. “A nice thing about this trial is that we're able to utilize the strength of our molecular tumor board,” says Sammons, who hopes to accrue up to 10 patients. “When patients get genomic sequencing as standard of care, MrT (DCI’s in- house electronic Molecular Registry of Tumors) will flag patients who have an ESR1 mutation and automatically email/notify the provider of their possible eligibility.”
Often, when patients enroll in a trial, they have little information about the drug’s potential side effects. In the case of lasofoxifene, its side effects are well characterized and appear to be quite well tolerated. “Lasofoxifene is very patient friendly,” Sammons says. “It actually improves vaginal dryness and sexual health, and strengthens bone.”
If the trial yields positive results, the next step will be to combine lasofoxifene with other targeted agents, Sammons says. “Endocrine therapy is the important backbone. We know that endocrine therapy works better, in general, when you add an optimal targeted agent such as CDK4/6, mTOR, or PIK3CA inhibitors.”
This bench-to-bedside story has been written, but it’s not finished. McDonnell and Sammons, for the sake of the thousands of metastatic breast cancer patients waiting for their next line of therapy, hope there will be a happy ending. “Treating metastatic breast cancer patients is my passion,” says Sammons. “Providing them the most up-to-date and compassionate care and developing novel therapies for advanced breast cancer that will improve outcomes are really why I am here at Duke.”
For more information about the ELAINE trial and enrollment at Duke Cancer Institute, contact the Breast Oncology Research team at 919.660.1278.
Sarah Sammons, MD, has done consulting for Novartis, Foundation Medicine, Sermonix, Astra Zeneca and Daiichi Sankyo. She receives research funding to her institution for clinical trials from Astra Zeneca, BMS, Eli Lilly, and Sermonix.
Donald McDonnell, PhD, is a consultant and has stock ownership in G1 Therapeutics and Zentalis. He receives royalties from Radius Health and could receive royalties through Duke associated with the licensing of lasofoxifene. He receives research support from Novartis.
Kaitlyn Andreano, PhD, Stephanie Gaillaird, MD, PhD, and Ching-Yi Chang, PhD, MSPH, could receive royalties through Duke associated with the licensing of lasofoxifene.