Interdisciplinary team shows ultrasound focused therapy allows drug to get past the blood-brain barrier
Breast cancer can devastate patients and their families, particularly when the cancer spreads to the brain and treatment is heartbreakingly limited. For years, scientists and clinicians have run into challenges when trying to deliver therapies that effectively zero in on metastatic cancer in the brain.
The Centre for Pharmaceutical Oncology (CPO) at the University of Toronto’s Leslie Dan Faculty of Pharmacy is on the cutting edge of developing technology aimed at advancing science and improving patient care. A team from the CPO and Sunnybrook Health Sciences Centre has made a world-first discovery after more than 20 years of painstaking work.
The team’s groundbreaking, Phase 1 clinical trial demonstrates a way to deliver antibody therapy to breast cancer that has metastasized to the brain. The collaboration has put brain cancers in the crosshairs of therapy that can target the metastatic tumours on the other side of the blood-brain barrier, which is what has frustrated scientists to date.
“I’m driven by the realization that cancer is a major issue facing all Canadians,” says CPO director Professor Raymond Reilly, whose innovative work with radiopharmaceuticals provided the critical juncture in improving the uptake of a drug into tumours in the brain.
Delivering therapy past the blood-brain barrier
While previous studies showed the blood-brain barrier could be safely opened, they did not show if medications cross this barrier in human patients. Reilly’s work provided the tool to demonstrate that a significant amount of the therapeutic drug can be seen getting into the brain by opening the blood-brain barrier with focused ultrasound.
The blood-brain barrier is a layer of cells that protects the brain but blocks the delivery of therapeutic drugs, which are too large to pass through. Reilly and his team at the CPO innovated by creating a radiopharmaceutical form of a drug commonly used to treat cancer that was easily tracked in the patient using nuclear medicine imaging.
It worked. This the first clinical trial in the world to demonstrate that focused ultrasound improves the uptake of the drug into tumours in the brain, the results recently published in Science Translational Medicine.
Radiopharmaceutical drugs are essential tools used in many nuclear medicine imaging procedures to diagnose a multitude of diseases including cancer, heart disease, infections, kidney disease, thyroid disorders and neurological diseases. Radiopharmaceuticals also have great potential for treating disease, especially cancer.
Educating pharmacists and advancing science for patients
The Leslie Dan Faculty of Pharmacy aims to educate and train future pharmacists and pharmaceutical scientists to make these kinds of health-care advances. The CPO was established to concentrate efforts and promote the collaborations needed to realize this type of goal. It focuses on translational research, which is a process to advance discoveries in lab-based science forward to clinical application, the point where patients are treated.
“This clinical trial represents hope for patients, and for us, that safe and effective brain treatments can be personalized and tailored,” says Dr. Nir Lipsman, a neurosurgeon at Sunnybrook who led the clinical trial.
Though there has been a dramatic increase in our knowledge of breast cancer that has metastasized to the brain in recent years, it has not yet translated into significant advances in prolonging life and survival in these patients. Treatment usually involves surgery, chemotherapy or focused radiation therapy.
Dr. Lipsman cautions that, while the Phase 1 trial demonstrates the safety of both focused ultrasound and the radio-labelled therapeutic developed by Prof. Reilly, it is still early days with this technology. This study does, however, provide promising data for one day eliminating the blood-brain barrier as an obstacle for the delivery of targeted therapy.
“Brain cancer is one of the most devastating conditions we treat,” Dr. Lipsman says. “Professor Reilly’s contribution in developing the radiopharmaceutical to visualize the uptake of the drug in the brain was integral. This radiopharmaceutical also has the future potential, using radiation, to treat breast cancer that has spread to the brain.”
This new method of treatment has promising implications for other forms of metastasized cancer. In fact, another study is in the works to deliver drugs for lung cancer that has spread to the brain, as lung cancer has a high risk of brain metastases.
Collaboration leads to scientific breakthrough
“It has been a long road and this breakthrough provides hope,” says Dr. Kullervo Hynynen, vice-president of research and innovation at Sunnybrook Health Sciences Centre. Dr. Hynynen is a key team member who in the early 2000s pioneered the areas of ultrasound to open the blood-brain barrier in pre-clinical models, ultimately leading to this discovery by the Sunnybrook and CPO team. “It will revolutionize how we treat brain disease.”
Dr. Hynynen’s overall goal to use technology to improve health care stretches back decades. He continued to refine the research that finally bloomed in this clinical trial through the collaboration among the CPO and Sunnybrook teams.
“Most people don’t understand the quality of cooperation needed to do such complicated work,” Dr. Hynynen says. “All of us being close to the University of Toronto campus and having the infrastructure here made it possible.”
When the opportunity for Sunnybrook and the team at CPO to collaborate on the trial emerged, the timing was perfect. The ideas interlocked. Professor Reilly already had developed a new radiopharmaceutical for a different clinical trial that didn’t go ahead. “You could call that a moment of discovery, in which we realized there was a great opportunity to work together on a very impactful study,” Prof. Reilly says. The opportunity to work directly with clinical teams providing patient care is what draws many aspiring biomedical researchers to the University of Toronto.
“Collaboration is the driving force behind scientific discovery and translational research,” says Micheline Piquette-Miller, associate dean of research at the Leslie Dan Faculty of Pharmacy. “Working with clinical teams and helping to solve some of the most challenging problems in medicine is a key focus of the research we lead.”
New and exciting work at the CPO promises hope
There is exciting work underway at the CPO that will affect the future of research and medicine. Researchers are developing new nanomedicine approaches to cancer treatment that could be more effective and less harmful to normal tissues. Some are studying the biological properties of cancer cells to identify new targets for anti-cancer drugs. Others are developing new diagnostic tools to aid in detecting a recurrence of cancer or to monitor response to treatment.
Prof. Reilly is now developing a radiopharmaceutical version of an immunotherapy drug used to treat lung cancer that will be used in a subsequent clinical trial of focused ultrasound in patients with lung cancer. His team is also developing other radiopharmaceuticals that could be used to treat breast cancer, glioblastoma multiforme, the most common and lethal brain tumour, as well as head and neck cancers.
Based at the Leslie Dan Faculty of Pharmacy, the CPO has also just completed construction of a first-in-Canada Good Manufacturing Practices (GMP) facility to prepare radiopharmaceuticals to a standard suitable for use in humans. The facility will be used to design and prepare new radiopharmaceuticals for future clinical trials.
“I am sure that almost everyone knows someone who has been diagnosed with cancer and sadly, almost all of us knew someone who has died from cancer,” Prof. Reilly says. “We established the Centre for Pharmaceutical Oncology to bring together researchers and their trainees to develop new diagnostics and therapeutics for cancer, advance these to clinical trials, and ultimately to patient care.”
Advertising feature produced by Globe Content Studio and the Centre for Pharmaceutical Oncology at the University of Toronto’s Leslie Dan Faculty of Pharmacy. The Globe’s editorial department was not involved.