Research by UBC professor lays groundwork for life-saving breast cancer treatment

A drug originally designed to prevent osteoporosis is now what it is, thanks to decades of basic research by Dr. Josef Penninger, professor of medicine at UBC School of Medicine and director of Life of the Life. It is expected to save and improve the lives of as many as one million breast cancer patients. scientific laboratory.

The achievement highlights how UBC scientists can develop effective new treatments and maximize the potential of existing drugs by studying the fundamental biological principles behind disease. to By advancing scientific discoveries from the lab to the clinic, UBC researchers bring life-changing treatments to patients everywhere.

The drug, called denosumab, was recently shown in a long-term phase III clinical trial to improve survival in postmenopausal women with hormone receptor-positive early-stage breast cancer receiving aromatase inhibitor therapy. It significantly improved patient quality of life by reducing fractures, a common side effect of treatment, by 50%. The results of the trial were recently reported. New England Journal of Medicine.

Denosumab is a monoclonal antibody developed by the US biopharmaceutical company Amgen to prevent bone loss. In the early 2000s, research by Dr. Penninger and his team revealed the therapeutic potential of denosumab and the startling relationship between the drug and breast cancer.

“More than 20 years ago, we started an experimental basis to uncover the potential of donosumab as a treatment for breast cancer patients,” says Dr. Penninger. “These results are very exciting and will help improve the lives of millions of patients. I am very proud of all the people in my lab.”

Discovery of relationship between osteoporosis and breast cancer

Denosumab works by binding to and inhibiting the activity of a protein called RANKL, which plays an important role in bone-resorbing cells called osteoclasts. By blocking her RANKL, denosumab reduces osteoclast activity, slows bone resorption, and helps increase bone density and prevent osteoporosis.

Dr. Penninger and his team began drawing a link between osteoporosis and HR-positive breast cancer when they generated the first RANKL ‘knockout’ mice in the late 1990s.

Knockout mice are laboratory mice that have been genetically engineered, or “knocked out,” to inactivate certain genes. To study the essential function of his RANKL protein in bone metabolism, Dr. Penninger’s team engineered mice lacking the gene required to produce RANKL protein.

However, to the researchers’ surprise, they found that RANKL-deficient mice failed to develop mammary glands during pregnancy, a process dependent on sex hormones.

“This has established an evolutionary link: how bone loss is regulated by sex hormones and how pregnant mammals activate RANKL to prepare breast tissue for lactation among other functions. It shows how to form,” says Dr. Penninger.

Based on this initial finding, Dr. Penninger’s team showed that RANKL plays an important role not only in progestin-induced breast cancer, but also in BRCA1 mutation-induced breast cancer.

“Additional researchers have demonstrated how RANKL regulates breast stem cells that respond to sex hormones, thereby promoting breast tissue growth throughout the menstrual cycle, particularly during pregnancy and lactation.” adds Dr. Penninger.

In breast cancer, RANKL promotes division of mammary epithelial cells and helps maintain stem cells that cause breast cancer.

dual benefit drug

According to the Breast Cancer Network of Canada, one in eight Canadian women will be diagnosed with breast cancer in her lifetime. An estimated 70-80% of these breast cancers are hormone receptor positive (HR positive), making them the most common breast cancer subtype.

The current standard of care for HR-positive breast cancer includes surgery and radiation therapy, followed by 5-7 years of treatment with an aromatase inhibitor. Aromatase inhibitors reduce sex hormones that promote the growth of new cancers, but can have serious negative effects on bone health, including increased risk of osteoporosis and fractures.

A currently published clinical trial led by the Austrian Breast and Colorectal Cancer Research Group will determine whether denosumab can help reduce these negative effects on bone health and improve breast cancer survival outcomes in two ways. was carried out to confirm the

“These results are incredibly exciting and will help improve the lives of millions of patients.”
Dr. Josef Penninger

Results showed that denosumab at the recommended therapeutic level for osteoporosis, 6 mg every 6 months, improved disease-free survival, bone metastasis-free survival, and overall survival in participants . It also effectively reduced fractures over the long term.

“Blocking RANKL in breast cancer patients reduces fractures by 50% and significantly improves quality of life, even at very low therapeutic doses,” said Dr. Penninger. “We know that RANKL promotes breast cancer cell proliferation, is a key mechanism behind bone loss, and also affects anti-cancer immunity and immunological rewiring during pregnancy. Our clinical results show that out of 1 million women diagnosed with breast cancer, blocking RANKL could save the lives of 50,000 women.”

Based on the data, the researchers behind the trial recommend denosumab be considered for routine clinical use in postmenopausal breast cancer patients receiving aromatase inhibitor therapy.

These trials were largely based on basic research published by the Penninger Institute, including Kong et al. Nature In 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 years.

Dr. Penninger is currently participating in a large international prevention trial evaluating denosumab in young women with BRCA1 mutations.