Researchers customizing treatments for cancer
Tools help personalize treatment in disease that morphs on each relapse
B.C. researchers are developing powerful new genomic tools to personalize cancer treatment, providing guidance about what drugs will work best and even figuring out which treatments might do more harm than good.
Christian Steidl, Marco Mara and David Scott of the B.C. Cancer Research Centre are focused on creating new diagnostic tests for cancers that maddeningly morph into different and more aggressive versions on each relapse.
Lymphoid cancers start in the immune system, and even after successful treatment can relapse into different forms, with a dizzying mortality rate. About 16,000 Canadians are diagnosed with Hodgkin’s lymphoma, non-Hodgkin’s, myeloma or leukemia each year. About 6,000 die.
There are dozens of variations of the disease and few tools in the diagnostic arsenal to guide treatment of the relapsing versions, which are the most deadly, said Steidl.
Without diagnostic tests specific to relapsing forms, doctors are hampered in their ability to choose the right treatments or to predict the outcome for their patients, meaning expensive drugs and therapies are applied without much certainty that they will help.
“We are filling a major knowledge gap and an unmet clinical need,” he said. “The (diversity) of the disease is a major problem to tackle. We need to classify them by looking into their genetic features to find more precise diagnostic tools and precise treatments.”
The research group has been awarded $11.9 million to genetically sequence relapsed tumours in a search for distinct biomarkers and shared vulnerabilities among the many sub-types of the disease, which could provide targets for personalized treatment.
They plan to develop genomicsbased tests and integrate them into treatment of patients who face a rapidly morphing disease that often leads to death.
Tony Griffen has certainly been through some twists and turns with his cancer.
What started as a relatively manageable case of slow-growing indolent lymphoma has morphed into an aggressive, relapsing form of the disease.
“The goal was never to cure my indolent lymphoma — there is no cure — but you know that when problems come up you have to have treatment,” he said. “It wasn’t much different from having diabetes.”
He received radiation in 1999, and in 2006 had his spleen removed, but after another relapse his slowpaced lymphoma transformed into large B-cell lymphoma.
“That is quite a different beast, and it’s quite unpleasant,” said Griffen, a pension administrator.
That beast invaded his bone marrow and began to crack his bones from the inside. Griffen underwent an advanced form of chemotherapy that successfully eradicated this latest incarnation of his cancer. He is feeling well again, for now, and participating in numerous research projects.
“What’s most important to realize is the (relapsing lymphomas) are dynamic,” said Steidl. “After a primary diagnosis, you can look at the same patient at relapse, it’s likely to be a completely different cancer.”
It is enormously challenging to treat a cancer that is a “moving target” because diagnostic information based on the original form of lymphoma in your patient becomes outdated so quickly, he said.
Choosing the right treatment is not only more cost-effective, it can also save the patient from the uncomfortable and sometimes debilitating side effects of cancer medications, according to Bruce Carleton, a professor at UBC’s faculty of medicine.
Carleton and fellow pharmacogenomics researcher Colin Ross are developing precision tools to predict adverse drug reactions, especially in childhood cancer patients.
A $9.9-million project will analyze more than 6,000 DNA samples from patients along with information about medications they were given and their outcomes to detect genetic markers that will predict bad drug reactions.
Such predictive information would be of enormous value to doctors treating patients with cancer, but also to the patients themselves, who are often not fully aware of the likelihood of debilitating side effects.
A patient facing 40 days of radiation should be able to weigh not just the likelihood of success, but also the likelihood that he might spend his final days in absolute misery if treatment fails, he said.
“Should it be about survival at any cost?” he asked. “No. What he worries about is that he’ll go through 40 days and be so sick that that is the end of his life. Maybe he’ll choose to spend the 40 days without (radiation) sickness, and if that’s the end, that’s the end.”
Prescription drug side effects are the fifth leading cause of death in North America, he said, adding that patients deserve to make informed decisions about treatments that can lead to lifelong illness, blindness, total hearing loss or death.
“When we are dealing with cancer, where we are using very potent pharmacologic agents in high doses to prolong life, it’s a critical part of an informed decision,” said Carleton. “If we want a patientcentred health system, we have to provide this information. We need to help patients meet their objectives, not just the doctors’ objectives.”
Adverse reaction data and genetic markers for susceptibility discovered by their work will be made available to researchers around the world. Testing tools developed will be put to use at 10 pediatric cancer centres across Canada.
The grants are part of an $80-million disbursement to B.C.based medical genomics projects by Genome Canada’s Large-Scale Applied Research Project competition, including contributions from Genome B.C.
Genome B.C. will lead a national $10-million project aimed at reducing a severe form of organ rejection in kidney transplant patients. Antibody-mediated rejection triggers the loss of a transplanted kidney in about 30 per cent of patients, causing them to return to dialysis as a treatment and often an early death. Dr. Paul Keown of the University of B.C. and an international team of scientists and clinicians will use genomic technologies to reduce the risk of AMR by better matching of patients and donors, monitoring the immune response after transplantation to better predict AMR, use personalizing drug treatments to prevent rejection.
As the use of genome-wide sequencing becomes more widespread as a diagnostic tool, the risk grows that the test will reveal genetic disorders and disease in patients that are not related to the original reason for testing.