St. Baldrick’s is all about shifting paradigms. When three men decided to shave heads at their industry’s March 17, 2000 St. Patrick’s Day party, they didn’t set out to change the landscape of childhood cancer research funding. But today the St. Baldrick’s Foundation is the largest non-government funder of childhood cancer research grants.
Twenty years later, the paradigm shifts keep coming, and Poul Sorensen, MD, PhD has been a part of several of them. Last month we joined some very special guests on a visit to his lab at the University of British Columbia, where he is a Professor of Pathology and holds the Johal Endowed Chair in Childhood Cancer Research.
Discovery of Gene Mutation Leads to a New Type of Drug
Just over twenty years ago Dr. Sorensen and his colleagues discovered a gene mutation that launched a new field in cancer biology. This gene alteration is called ETV6-NTRK3, and it was first found in infantile fibrosarcoma, a soft-tissue sarcoma that affects about twenty infants a year in the U.S. This genetic marker was later also found by the Sorensen team in a kidney cancer, then in a rare type of breast cancer — and by now ETV6-NTRK3 and similar alterations are known to occur in at least 25 types of cancers that strike children and adults.
“Genetics are simpler in kids,” says Dr. Sorensen. “It’s harder to come up with targeted therapies for adults, because they have far more genetic mutations. But this is a good example of pediatric cancer research affecting adults, too.”
In fact, these gene fusions are found in about one percent of all cancer patients – adults and children. The discovery ultimately led to the 2018 FDA approval of the first drug not for a specific type of cancer, but to target a key genetic driver of cancer. The drug is called larotrectnib, or Vitrakvi.
“That’s the kind of success story we want,” says Dr. Sorensen, speaking of his current work. “Only we want it to move faster.”
His lab’s role is not to create a drug, but to do the pre-clinical discovery work that is the basis for others to create new therapies for kids. Dr. Sorensen is now part of two major research projects to do just that, with funding from St. Baldrick’s.
Discovery in Immunotherapy With the Dream Team
Dr. Sorensen is a principal investigator on the St. Baldrick’s – Stand Up 2 Cancer Pediatric Cancer Dream Team, which focuses on finding new immunotherapies for high-risk childhood cancers. His group runs several major components of the discovery work, including molecular pathology.
His lab team in Vancouver joins another in Toronto and seven U.S. institutions, all working closely together to shift paradigms in childhood cancer treatment. The scientists meet regularly and talk frequently between meetings, exchanging ideas and discoveries to use a better understanding of genomics to develop therapies that use the patients’ own immune systems to fight cancer.
“For the Vitrakvi story, we didn’t have the incredible network we now have in the Dream Team,” Dr. Sorensen says. “I’ve never been part of anything this powerful. We hope this helps us speed up the process from the twenty years it took to get Vitrakvi, to maybe five years.”
The Dream Team is indeed moving quickly, having treated more than 1000 patients on 50 clinical trials already. It played a major role in getting the Kymriah, the first gene therapy, approved in the U.S.. As a result, children with a particularly difficult type of leukemia — like St. Baldrick’s 2020 Ambassador Austin — are alive today, who otherwise had no hope.
Patrick Sullivan, Patient Advocate for the Dream Team, says Dr. Sorensen and his group are unique in the skill set they bring to looking for new targets. “This is a story not just of success, but of trial and error and failure and then success.” Patrick’s son Finn died of rhabdomyosarcoma in 2008, years before the Dream Team began. Today, Patrick knows of a boy in Texas who is surviving the same disease, because of a Dream Team clinical trial.
Discoveries in Ewing Sarcoma
Joining us for the visit to Dr. Sorensen’s lab was a very special family including a teenage girl currently fighting Ewing sarcoma, and anonymous donors who gave $1 million in her honor.
That gift allowed the St. Baldrick’s Foundation to issue a Request for Applications (RFA) outside of regular grant cycles, inviting researchers to submit their best ideas for projects specifically aimed at shifting paradigms in Ewing sarcoma. The highest scoring application would receive three years of funding.
That grant went to Dr. Poul Sorensen and his lab, including his co-investigator Dr. Mads Daugaard at the University of British Columbia. Dr. Daugaard is also a member of the Dream Team, and in 2019 he was a recipient of the prestigious St. Baldrick’s Robert J. Arceci Innovation Award.
Ewing sarcoma is an aggressive bone and soft tissue tumor that occurs in children and young adults. At diagnosis, 25-30% of patients already have metastases, cancer that has spread and is therefore more difficult to cure. It has proven largely resistant to conventional immunotherapy, and new treatment approaches are sorely needed.
Dr. Sorensen’s proposal involved three different strategies to target Ewing sarcoma. The first utilizes an experimental drug-candidate to inhibit the specific fusion proteins that drive Ewing sarcoma tumor development. The second will use an antibody that specifically binds to IL1RAP, a highly expressed molecule on the surface of Ewing sarcoma cells, linking this antibody to toxins to target and kill the cancer cells. The last is to recruit natural killer (NK) immune cells and prime them to attack the tumor.
“The fusion protein makes cells proliferate, but it’s also important to understand metastasis in Ewing sarcoma,” says Dr. Sorensen. “We need to understand more than just the fusion protein, but also how the tumor spreads, how it moves to distant locations in the body. So this grant has three strategies by design, to learn more to target Ewing sarcoma in several ways. To be honest, we don’t know which will work best, but are of course open to combinatorial approaches.”
Since Ewing sarcoma researchers are a small tight-knit group, they talk frequently, Dr. Sorensen says. What he and his colleagues learn from this grant, made possible by the generosity of an anonymous donor, will reach many others, and we do hope it will result in a paradigm shift in the treatment of this disease.
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