A drug originally designed to prevent osteoporosis is now expected to save and improve the lives of millions of people with breast cancer, thanks in part to decades of foundational research by Dr. Josef Penninger, a professor in UBC’s Faculty of Medicine and director of the Life Sciences Institute.
The achievement highlights how UBC scientists are developing effective new treatments — and unlocking the full potential of existing drugs – through research into the fundamental biological principles behind disease. By advancing scientific discoveries from the lab to the clinic, UBC researchers are bringing life-changing treatments to patients everywhere.
The drug, called Denosumab, was recently shown in a long-term Phase 3 clinical trial to improve survival among postmenopausal women with hormone receptor-positive early breast cancer receiving aromatase inhibitor treatment. Moreover, the drug markedly improved patients’ quality of life by reducing broken bones by 50 per cent, a common side effect of breast cancer treatment. The results of the trial were recently reported in The New England Journal of Medicine.
Denosumab is a monoclonal antibody developed by American biopharmaceutical company Amgen to prevent bone loss. In the early 2000s, research by Dr. Penninger and his team revealed the therapeutic potential of Denosumab, as well as the drug’s surprising connections with breast cancer.
“More than two decades ago we started the experimental groundwork that revealed Donosumab’s potential as a treatment for breast cancer patients,” says Dr. Penninger. “These results are incredibly exciting and will help improve the lives of millions of patients. I am very proud of all the people in my lab over the years who did that work and helped pave the way for this achievement.”
Discovering the link between osteoporosis and breast cancer
Denosumab works by binding to and inhibiting the activity of a protein called RANKL, which plays a key role in bone-resorbing cells called osteoclasts. By blocking RANKL, denosumab reduces the activity of osteoclasts and slows down bone resorption, helping to increase bone density and preventing osteoporosis.
Dr. Josef Penninger
Dr. Penninger and his team began to draw the connection between osteoporosis and HR-positive breast cancer when they generated the first RANKL “knock-out” mice in the late 1990s.
A knockout mouse is a laboratory mouse that has been genetically engineered to have certain genes deactivated, or “knocked-out”. Dr. Penninger’s team engineered mice that lacked the genes necessary to produce the RANKL protein in an effort to study the protein’s essential function in bone metabolism.
However, to the researchers’ surprise, they discovered that the RANKL-deficient mice failed to develop a lactating mammary gland in pregnancy – a process that depends on sex hormones.
“This proved an evolutionary link: showing how bone loss is regulated by sex hormones, and how pregnant mammals activate RANKL to form breast tissue for lactation among other functions,” says Dr. Penninger.
Based on this initial finding, Dr. Penninger’s team went on to show that RANKL played a key role in progestin-driven breast cancer, as well as breast cancer driven by BRCA1 mutations.
“Further researcher revealed how RANKL controls the stem cells in the breast that respond to sex hormones and thereby drives growth of the breast tissue at every menstruation cycle and in particular in pregnancy and lactation,” adds Dr. Penninger.
In the case of breast cancer, RANKL spurs mammary epithelial cells to divide, and helps to maintain the stem cells that give rise to breast tumours.
A dual benefit drug
One in eight Canadian women will be diagnosed with breast cancer in their lifetime according to the Canadian Breast Cancer Network. An estimated 70 to 80 per cent of these breast cancers are hormone receptor-positive (HR-positive), making it the most prevalent breast cancer subtype.
The current standard treatment for HR-positive breast cancer involves surgery and radiation, followed by treatment with aromatase inhibitors for 5 to 7 years. While aromatase inhibitors diminish sex hormones that drive new cancer growth, they can have serious adverse effects on bone health, including increased risk of osteoporosis and fractures.
The now-published clinical trial, led by the Austrian Breast and Colorectal Cancer Study Group, was conducted to see if Denosumab could help in two ways: by reducing these negative effects on bone health, while also improving breast cancer survival outcomes.
“These results are incredibly exciting and will help improve the lives of millions of patients.” Dr. Josef Penninger
The results reveal that 6 mg of Denosumab every six months — the recommended treatment level for osteoporosis — improved disease-free survival, bone metastasis-free survival, and overall survival among participants. It also effectively reduced bone fractures over the long term.
“Blocking RANKL in breast cancer patients reduces broken bones by 50 per cent, massively improving their quality of life, and even at a very low treatment dose,” says Dr. Penninger. “We now know that RANKL drives breast cancer cell growth, is the critical mechanism behind bone loss, and has also an effect on anti-cancer immunity and immunological rewiring in pregnancy. These clinical results in patients show how blocking RANKL could save the lives of 50,000 women among one million women with the diagnosis of breast cancer.”
Based on the data, the researchers behind the trials are recommending that Denosumab be considered for routine clinical use in postmenopausal breast cancer patients receiving aromatase inhibitor therapy.
These trials were largely based on the foundational research published by the Penninger laboratory, including Kong et al. Nature 1999, Fata et al. Cell 2000, Jones Nature 2006, Schramek et al. Nature 2010, Sigl et al. Cell Research 2016, and Paolino et al. Nature 2021.
Dr. Penninger is now part of a large international prevention trial evaluating Denosumab in young women who carry BRCA1 mutations.
MILWAUKEE (AP) — Whooping cough is at its highest level in a decade for this time of year, U.S. health officials reported Thursday.
There have been 18,506 cases of whooping cough reported so far, the Centers for Disease Control and Prevention said. That’s the most at this point in the year since 2014, when cases topped 21,800.
The increase is not unexpected — whooping cough peaks every three to five years, health experts said. And the numbers indicate a return to levels before the coronavirus pandemic, when whooping cough and other contagious illnesses plummeted.
Still, the tally has some state health officials concerned, including those in Wisconsin, where there have been about 1,000 cases so far this year, compared to a total of 51 last year.
Nationwide, CDC has reported that kindergarten vaccination rates dipped last year and vaccine exemptions are at an all-time high. Thursday, it released state figures, showing that about 86% of kindergartners in Wisconsin got the whooping cough vaccine, compared to more than 92% nationally.
Whooping cough, also called pertussis, usually starts out like a cold, with a runny nose and other common symptoms, before turning into a prolonged cough. It is treated with antibiotics. Whooping cough used to be very common until a vaccine was introduced in the 1950s, which is now part of routine childhood vaccinations. It is in a shot along with tetanus and diphtheria vaccines. The combo shot is recommended for adults every 10 years.
“They used to call it the 100-day cough because it literally lasts for 100 days,” said Joyce Knestrick, a family nurse practitioner in Wheeling, West Virginia.
Whooping cough is usually seen mostly in infants and young children, who can develop serious complications. That’s why the vaccine is recommended during pregnancy, to pass along protection to the newborn, and for those who spend a lot of time with infants.
But public health workers say outbreaks this year are hitting older kids and teens. In Pennsylvania, most outbreaks have been in middle school, high school and college settings, an official said. Nearly all the cases in Douglas County, Nebraska, are schoolkids and teens, said Justin Frederick, deputy director of the health department.
That includes his own teenage daughter.
“It’s a horrible disease. She still wakes up — after being treated with her antibiotics — in a panic because she’s coughing so much she can’t breathe,” he said.
It’s important to get tested and treated with antibiotics early, said Dr. Kris Bryant, who specializes in pediatric infectious diseases at Norton Children’s in Louisville, Kentucky. People exposed to the bacteria can also take antibiotics to stop the spread.
“Pertussis is worth preventing,” Bryant said. “The good news is that we have safe and effective vaccines.”
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AP data journalist Kasturi Pananjady contributed to this report.
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The Associated Press Health and Science Department receives support from the Robert Wood Johnson Foundation. The AP is solely responsible for all content.
How a sperm and egg fuse together has long been a mystery.
New research by scientists in Austria provides tantalizing clues, showing fertilization works like a lock and key across the animal kingdom, from fish to people.
“We discovered this mechanism that’s really fundamental across all vertebrates as far as we can tell,” said co-author Andrea Pauli at the Research Institute of Molecular Pathology in Vienna.
The team found that three proteins on the sperm join to form a sort of key that unlocks the egg, allowing the sperm to attach. Their findings, drawn from studies in zebrafish, mice, and human cells, show how this process has persisted over millions of years of evolution. Results were published Thursday in the journal Cell.
Scientists had previously known about two proteins, one on the surface of the sperm and another on the egg’s membrane. Working with international collaborators, Pauli’s lab used Google DeepMind’s artificial intelligence tool AlphaFold — whose developers were awarded a Nobel Prize earlier this month — to help them identify a new protein that allows the first molecular connection between sperm and egg. They also demonstrated how it functions in living things.
It wasn’t previously known how the proteins “worked together as a team in order to allow sperm and egg to recognize each other,” Pauli said.
Scientists still don’t know how the sperm actually gets inside the egg after it attaches and hope to delve into that next.
Eventually, Pauli said, such work could help other scientists understand infertility better or develop new birth control methods.
The work provides targets for the development of male contraceptives in particular, said David Greenstein, a genetics and cell biology expert at the University of Minnesota who was not involved in the study.
The latest study “also underscores the importance of this year’s Nobel Prize in chemistry,” he said in an email.
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The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.
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