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 groundbreaking research by Dr. Josef Penninger, a professor at the UBC School of Medicine and director of the Life Science Institute .
The achievement highlights how UBC scientists are developing new effective treatments – and unlocking the full potential of existing drugs – by exploring the basic biological principles behind disease. By advancing scientific discovery from the laboratory 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. The drug also significantly improves patients’ quality of life by reducing broken bones by 50 percent, 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 the 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 links to breast cancer.
“More than two decades ago, we began the experimental work that revealed the potential of donozumab 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 have done this 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 osteoclast activity and slows bone resorption, helping to increase bone density and prevent osteoporosis.
Dr. Joseph Penninger
Dr. Penninger and his team began to establish the link between osteoporosis and HR-positive breast cancer when they generated the first RANKL “knockout” mice in the late 1990s.
A knockout mouse is a laboratory mouse that has been genetically engineered to have certain genes disabled or “knocked out”. Dr. Penninger’s team engineered mice that lacked the genes needed to produce the RANKL protein in an attempt to study the protein’s primary function in bone metabolism.
However, to the researchers’ surprise, they found that RANKL-deficient mice failed to develop a lactating mammary gland during pregnancy, a process that depends on sex hormones.
“This proved an evolutionary link: it shows 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 plays a key role in progestogen-induced breast cancer as well as in breast cancer caused by BRCA1 mutations.
“Additional research revealed how RANKL controls stem cells in the breast that respond to sex hormones and thereby stimulate the growth of breast tissue with each menstrual cycle and particularly during pregnancy and lactation,” adds Dr. Penninger.
In the case of breast cancer, RANKL stimulates the division of mammary epithelial cells and helps maintain the stem cells that give rise to breast tumors.
A medicine with double benefits
One in eight Canadian women will be diagnosed with breast cancer in her lifetime, according to the Canadian Breast Cancer Network. Approximately 70 to 80 percent of these breast cancers are hormone receptor positive (HR-positive), making it the most common subtype of breast cancer.
Current standard treatment for HR-positive breast cancer includes surgery and radiation followed by aromatase inhibitor treatment for 5 to 7 years. While aromatase inhibitors reduce the sex hormones that stimulate new cancer growth, they can have serious adverse effects on bone health, including an increased risk of osteoporosis and fractures.
The now-published clinical trial, led by the Austrian Breast and Colorectal Cancer Research Group, was conducted to see if Denosumab could help in two ways: by reducing these negative effects on bone health while improving outcomes for breast cancer survival.
“These results are incredibly exciting and will help improve the lives of millions of patients.” Dr. Joseph Penninger
The results revealed that 6 mg of Denosumab every six months — the recommended level of treatment for osteoporosis — improved disease-free survival, bone metastasis-free survival, and overall survival among participants. It also effectively reduces bone fractures in the long term.
“Blocking RANKL in breast cancer patients reduced the number of broken bones by 50 percent, significantly improving their quality of life even at a very low treatment dose,” says Dr. Penninger. “We now know that RANKL stimulates the growth of breast cancer cells, is the critical mechanism behind bone loss, and also has an effect on anti-cancer immunity and immunological readjustment during pregnancy.” These clinical results in patients show how blocking RANKL could save the lives of 50,000 of the one million women diagnosed with breast cancer.
Based on the data, the trial investigators recommend that Denosumab be considered for routine clinical use in postmenopausal breast cancer patients receiving aromatase inhibitor therapy.
These attempts are largely based on seminal research published by the Penninger lab, 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.
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