Dr. Luc Berthiaume doesn’t give up easily.
For the last 25 years, the University of Alberta cell biologist has been working “outside the box” in a relatively unexplored area of cancer research — and convincing national funding agencies and pharmaceutical firms to back this research has been a challenge.
In graduate school, Berthiaume became fascinated by a biological process called myristoylation, where proteins are modified by a fatty acid named myristate. During his post-doc studies, he was further intrigued by the idea that an inhibitor of this process could become the cornerstone of a new form of anti-cancer drug, and this has been one of his major focuses ever since.
Today, his laboratory at the University of Alberta is one of only five in the world focusing on the study of myristoylation.
“[To advance cancer research,] you need to look somewhere other than where everyone else is looking,” Berthiaume says. “But by doing something novel, you complicate your own life because no one knows what to do in terms of evaluating your research. Fortunately, I am very persistent.”
His perseverance has paid off
Later this year, or early in 2021 (due to a pandemic-related delay), clinical trials will begin on a promising new cancer drug, known as PCLX-001, based on myristoylation inhibition research done in Berthiaume’s lab. Canadian cancer centres in Toronto, Vancouver and the Cross Cancer Institute in Edmonton will take part.
Early studies of PCLX-001 were very promising. Thanks in large part to $1.4 million from the Alberta Cancer Foundation, Berthiaume’s lab was able to first test the drug in the lab and on pre-clinical models. In four of five studies, the lead compound completely eradicated blood cancer tumours, and in the fifth study, it removed 95 per cent of the tumours. Up to 25 days later, none of the tumours had returned once the drug treatment ceased.
Moreover, the drug selectively kills cancer cells while sparing normal cells, “the holy grail of cancer therapy,” as Berthiaume puts it. He is hopeful there will be similar results in humans.
“We are really indebted to the Alberta Cancer Foundation and especially all the donors who gave money to the Foundation because they are all part of this promising therapy,” he says.
The human trials are being funded by $5 million from angel investors, $2.3 million in donations from the researchers themselves, their family and friends, and almost $500,000 raised during the World’s Longest Baseball Game charity event in Sherwood Park last summer.
The Phase 1 trials will evaluate the safety of the drug, focusing on those with advanced lymphoma, as well as a smaller group of patients with breast, lung and other cancers.
Hooked on Science
Berthiaume, whose first language is French, describes research as his raison d’être or “reason for being.” He was born in Montreal and raised by hard-working parents who wanted him to study medicine. “But,” he says, “as an extremely curious child and later a fairly adventurous adult, I was always more interested in understanding the causes of diseases and finding cures for diseases, more than personally treating the patients directly.”
As a teenager, Berthiaume had a knack for biology and chemistry. When he received 100 per cent on a cell biology exam in Grade 9, his teacher told him it was the first time in 35 years of teaching that she’d given a perfect mark. The class gave him a standing ovation and he was hooked on the idea of a career in science from that point on.
Berthiaume did his undergraduate studies in biochemistry at the University of Sherbrooke and went on to do his PhD in biochemistry at the same institution, completing his doctorate in 1991. From 1991 to 1995, he did post-doctoral studies at the Memorial Sloan Kettering Cancer Center in New York, one of the top cancer centres in the world. The focus of his research there was the modification of proteins by fatty acids and what role that plays in cancer.
After finishing his studies, Berthiaume had several job offers and made the decision to move to Edmonton and continue his work at the University of Alberta.
“I’ve never regretted it, although it was an adaptation,” he says. “But now Alberta is home to me.” He celebrated 25 years at the university on July 1. In addition to his research work, Berthiaume teaches a senior-level course called Cell Biology of Diseases.
In the early years, Berthiaume’s team studied the role of protein fatty acid modification in cellular targeting, signalling and metabolism. They had a significant breakthrough about 10 years ago when they hypothesized that the levels of enzymes carrying out the myristoylation process (called NMT1 and NMT2 enzymes) could be altered in cancerous cells. They discovered that blood cancer cells carried only NMT1, rather than the two enzymes found in healthy cells. If they could find an NMT inhibitor to target cells with only NMT1, they would, in effect, be killing cancer cells while sparing healthy cells.
After scouring the literature, Berthiaume found a team at the University of Dundee in Scotland that had developed an NMT inhibitor to treat African sleeping sickness. He contacted the principal researcher, Dr. Paul Wyatt, about obtaining some of the compound, called DDD85646, to test its ability to kill cancer cells. Royalty-sharing arrangements were made between the two universities and the compound was shipped to Edmonton, where laboratory studies quickly began. After obtaining promising results with DDD85646, Berthiaume and his team asked Dr. Wyatt if there was an analog of the compound more specific towards human NMTs, which there was, and it was called DDD86481. It is this compound, which Berthiaume’s team renamed PCLX-001, that will be tested on patients in the upcoming clinical trials.
Dr. John Mackey, an oncologist and director of clinical trials at the Cross Cancer Institute, has partnered with Berthiaume to set up Pacylex, a University of Alberta spinoff company that is developing PCLX-001. While most new drug development projects have about a one-in-a-million chance of being successful, because the Berthiaume lab and Pacylex have successfully completed five of the first seven steps of taking a drug to market, Mackey believes PCLX-001 now has a roughly one-in-three chance of having a positive impact on the lives of cancer patients. He credits Berthiaume for sticking with his ideas.
“Dr. Berthiaume is very much an independent thinker,” says Mackey. “He has devoted his career to studying a relatively unexplored aspect of cancer biology that is far from the mainstream. And despite the considerable skepticism with which his ideas have been met over the years, it seems he is right – inhibitors of myristoylation very much deserve to be tested in people with cancer.”
In the future, Berthiaume hopes to investigate other applications for PCLX-001, including more research into its action in breast and lung cancers, and even some diseases other than cancer. For now, he is happy to be back in the lab after a six-week COVID-related pause. He has already received a $1 million Award in Hematological Cancers’ Research in Memory of Dr. Rachel Mandel in 2020, which will allow his team to complete their laboratory studies to understand the mechanism of action of PCLX-001 in lymphoma and to expand their research into its effects on other blood cancers, such as leukemia. The award given by the Alberta Cancer Foundation, and aligned with CRINA’s Rachel Mandel Scholarship in Lymphoma and Other Blood Cancers, is named for Edmonton optometrist Dr. Rachel Mandel (the daughter of former Edmonton mayor Stephen Mandel), who passed away in 2017 of lymphoma.
Berthiaume is excited to get the upcoming Phase 1 clinical trials underway with no further delays. The trials will likely last one to one and a half years. Phase 2 research further evaluating the efficacy of PCLX-001 on lymphoma and leukemia patients will probably take another $40 million in funding. But he doesn’t seem fazed by that prospect.
“I’m somewhat fearless,” he says. “I’m not afraid to do stuff that no one else has done.”
Questions with Dr. Luc Berthiaume
Describe what you do in 10 words or less.
Fight cancer through research, education and a company I co-founded.
What’s challenging about what you do?
Scientifically speaking, there are only five laboratories in the entire world that are focused mainly on studying myristoylation as a research topic. This makes getting grants through the peer-review process very difficult. So I guess that makes me one in a billion!
Where do you get your best ideas?
Most often I get new ideas in my office after seeing new results from my trainees or after reading a cutting-edge scientific article. Some ideas also come to me when I sleep during periods of stress.
If you weren’t a cell biologist, what would you be?
If I absolutely have to name something, it would have to include some aspect of science, research and discovery, so something like archaeology or palaeontology could work. Alternatively, I played varsity soccer and was offered some professional contracts. Life as a professional soccer player could have been fun, too!
What motivates you?
My ardent desire to make a difference in this world though education, research and developing a cure for cancer(s) to help others.
Why does your research matter?
The odds of developing cancer through one’s lifetime are about one in three. By developing a new cancer therapy, we could have a significant humanitarian impact, first locally in Alberta then globally. From a practical viewpoint, when successful, our new drug, originating from our basic research program in the department of Cell Biology at the University of Alberta, will hopefully create jobs locally and contribute much-needed diversification of the Alberta economy.