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The ‘incredible’ way the HPV virus causes cancer and what that means for treating it

OICR-supported research could open new avenues to treat cancers of the cervix, head and neck.

The human papillomavirus (HPV) is the driving force behind most cancers of the cervix, head and neck thanks to its unique ability to hijack the human chromosome. 

OICR-supported research has uncovered new details about how that hijacking happens and could provide a roadmap for how to stop it.

“HPV has the incredible ability to integrate itself into a human’s chromosomes,” says Dr. Michael Hoffman, a Senior Scientist at Princess Margaret Cancer Centre who led the study with colleagues Dr. Mathieu Lupien (an OICR Investigator) and Dr. Scott Bratman. “Our study focuses on how that integration, and where it takes place, can contribute to cancer.”

The study, published in Genome Biology, describes how HPV DNA inserts itself into its host’s genome and ‘rewires’ the activity of nearby genes. 

“When the rewired genes normally play a role in stopping abnormal growth, this can result in cancer,” Hoffman says. 

The virus works on human cells by ‘loosening’ chromatin, a ‘package’ of DNA which is normally tightly packed into a cell’s nucleus. This gives the virus access to a cell’s DNA and allows it to make changes to the proteins that regulate cell growth.

“We found that by hijacking the epigenetic machinery of the cell, HPV can induce everlasting changes in a chromosome that predispose to cancer,” says Dr. Mehran Karimzadeh, first author of the study, who performed the research while a PhD student at Princess Margaret Cancer Centre.

Hoffman says his group’s findings about HPV changing human DNA are unique from other studies into HPV and cancer, which have focused largely on the role of HPV’s own DNA. By describing this pathway through which HPV causes certain cancers, this new study could help discover new ways to treat those cancers.

“What we discovered in this study, when combined with DNA sequencing technology, could lead to better assessment of cancer prognosis and more informed treatment decisions,” Hoffman says.

Paying it forward with a patient perspective

Carla Bossart-Pletzer joined OICR’s Patient and Family Advisory Council to help others with cancer overcome the odds, just like she did.

In a matter of a few weeks, Carla Bossart-Pletzer went from visiting the emergency department about a high fever and stubborn rash on her breast to learning she had one of the most aggressive forms of breast cancer.

It was a whirlwind with a shocking result: inflammatory triple negative breast cancer, which has a much lower survival rate than other types of breast cancer.

But Bossart-Pletzer barely had a chance to be shocked. Within days, she was starting chemotherapy to try and shrink her tumour before surgery — a new treatment approach that had only recently become the standard of care.

In the meantime, her scans for metastatic cancer came back clean. By the time she had surgery six months later, doctors found her tumour had shrunk to a fraction of its former size and no evidence of cancer remained her in lymph nodes.

In many ways, everything went right with Bossart-Pletzer’s cancer treatment. Her healthcare providers acted quickly, and her treatment did exactly what it was supposed to.

“All the systems went exactly as they should,” says Bossart-Pletzer, a designer and illustrator based in Sudbury. “Here I am, 18 months later, with no evidence of cancer.”

But her experience with cancer was far from perfect. She still had to go through a year and a half of aggressive treatment that left her with lingering side effects, and she found that the way things operated in the hospitals and cancer centres she visited didn’t feel quite right.

She’s also very aware that things could have gone very differently under other circumstances.

“I have this feeling. Maybe it’s survivor’s guilt,” Bossart-Pletzer says. “But I look at what cancer research has done for me, and how it has changed my future. Now, what can I do to ensure that other people have the same results?”

Just a year and a half since her diagnosis, Bossart-Pletzer is taking action to answer that question by becoming a Patient Advisor and building patient involvement at Health Sciences North in Sudbury and, more recently, joining OICR’s Patient and Family Advisor Council (PFAC). OICR News recently asked her about her early days on PFAC and what she hopes to achieve.

You mentioned that the success of your cancer treatment motivated you to want to give back. Can you tell us more about that?

I think a lot about why things worked so well for me. I know part of it is because I lived in Sudbury, where we have an impressive cancer centre and I was well connected to healthcare people. I also know it’s partly because, as a white woman, I was taken seriously by healthcare providers and was treated expeditiously. Because the reality is, when you look at the statistics with inflammatory breast cancer, it disproportionately affects women of colour in their thirties and forties and is almost always diagnosed at the metastatic stage. So, there’s a certain obligation I feel to make sure that system works as well for others as it did for me.

Is there any area of cancer research that you’re particularly interested in?

I’m still in the early days with OICR, but I’m finding I’m really interested in improving access to clinical trials. As somebody from Northern Ontario, it sometimes seems that people forget that Ontario continues north of Barrie. There’s a huge population of people up here that don’t have access to clinical trials that could help save their lives.

What other impact would you like to have as a patient partner?

I think there’s a misconception that cancer only happens to people under 18 or over 65. But there are unique challenges that come with being a young adult with cancer, and I’d like to bring more attention to them.

For example, I’m only just now able to return to work after a year and a half of treatment. Add that to being a mother in my 30s coming out of a pandemic, and it means every dollar is important. Unfortunately, I had to pay out of pocket for some parts of my treatment. And I was sometimes faced with choices like: do I pay for chemo pills, or do I put my kids in soccer?

How has being a mother influenced the way you approach being a patient partner?

As part of my breast cancer diagnosis, I found out that I have the BRCA1, MSH-6 and ATM genetic mutations, which are hereditary. I have a four-year-old daughter. What is her life going to look like in the future? What decisions is she going to have to make when she turns 18 because she’s scared of getting cancer like her mom? Will I still be alive to help her make those decisions? I don’t know. So, I’m in this window of opportunity to do what I can to make things better for her and for others who may get this cancer in the future.

Fecal transplants bolster melanoma treatment in unique clinical trial

A trial led by OICR Investigator Dr. Saman Maleki used fecal microbiota transplants (FMT) to improve how melanoma patients respond to immunotherapy.

People with advanced melanoma who get a fecal transplant before starting immunotherapy could have better results from treatment, according to a promising clinical trial.

In the trial, published in Nature Medicine, patients were given what is called a fecal microbiota transplant (FMT) from a healthy donor in the hopes of improving their gut health before starting immunotherapy, a new type of treatment that stimulates the body’s immune system to kill cancer.

Currently, immunotherapy works for less than half of patients with advanced melanoma, and side effects can be severe. But earlier research showed a healthy gut microbiome triggers a stronger response to immunotherapy.

“We need treatments for melanoma that we can add to existing immunotherapies to improve overall patient response without adding too much toxicity,” says lead investigator Dr. Saman Maleki, a Scientist at Lawson Health Research Institute, Assistant Professor at Western University’s Schulich School of Medicine and an OICR Investigator. “Our study shows that FMT could be a safe and effective option.”

A total of 20 patients from across Ontario and Quebec were recruited for the trial at the Lawson Health Research Institute, the Centre hospitalier de l’Université de Montréal (CHUM) and the Jewish General Hospital (JGH). They were given FMT in capsule form one week before starting immunotherapy.

About 65 per cent of participants saw their cancer improve during the trial, which is higher than the response rate expected from immunotherapy alone (30-40 per cent). Four patients had their cancer disappear completely during the trial — a result Maleki calls ‘remarkable’.

“We are very encouraged by the strong response profile that we observed in this cohort of patients,” he says.

The results also showed that using FMT this way is safe and doesn’t add any additional side effects beyond what is expected from immunotherapy. In fact, FMT may help reduce some immunotherapy side effects, and that potential is being explored in another different clinical trial.

Maleki and colleagues are already working on a larger clinical trial to further explore the effect of FMT and immunotherapy on melanoma. Similar studies are also underway using fecal transplants to treat renal cell carcinoma, lung cancer and uveal melanoma, and there are plans for trials that target pancreatic cancer and breast cancer.

“When I came up with the idea of prospective microbiome modulation in cancer patients in 2016, there was not much enthusiasm in the oncology community,” Maleki says. “Now, we’ve opened the door to using FMT in other cancers in early settings, which could potentially change how cancer patients are treated with immunotherapy drugs in the future.”

This research is supported in part through donor funding from London Health Sciences Foundation, Western University, the Lotte and John Hecht Memorial Foundation, the JGH Foundation, Canadian Cancer Society’s Impact Grant program, The Terry Fox Foundation and OICR’s Investigator Awards. More information is available in an announcement from the Lawson Health Research Institute.

New framework aims to drive innovation by making health data management ‘FAIR’

OICR’s Dr. Mélanie Courtot was part of a global effort to make data more findable, accessible, interoperable and reusable (FAIR).

Health data holds the key to overcoming major public health challenges, but only if it is accessible when people need it.

The world learned this lesson the hard way during the COVID-19 pandemic, when problems like missing data, service incompatibility and data access restrictions delayed research that could have helped the global public health response.

But an international collaboration, led in part by OICR’s Dr. Mélanie Courtot, has developed a toolkit to help break down current barriers to accessing clinical and molecular data.

The FAIRplus consortium recently launched the FAIRification framework, an adaptable, easy-to-use guide for health and research organizations to make data more findable, accessible interoperable and reusable (FAIR).

“Data that can’t be found is data that can’t be reused,” said Courtot, who is Director of Genome Informatics and Principal Investigator at OICR, Assistant Professor of Medical Biophysics at the University of Toronto, and an author of the FAIRification framework. “The FAIRification framework provides practical, actionable steps for data owners to increase the value of their work and make their results available to the community.”

In addition to the framework, the consortium also created a FAIR ‘cookbook’ to support organizations in implementing FAIR principles. With the tools they created, the consortium has already applied the framework to clinical interventional study datasets, data generated in the lab, as well as real-world and clinical observational data.

Courtot’s involvement in the FAIRplus consortium began as part of her former role as Metadata Standards Coordinator for the European Bioinformatics Institute (EMBL-EBI), one of 21 partner organizations from academia and industry that contributed to the project.

She says using the framework to implement FAIR principles could help drive important innovations in health research and care.

“Standardized interoperable data benefits the global research community who can link different projects and outcomes, and ultimately benefits human health,” she says.

This story was adapted from an article by the European Bioinformatics Institute (EMBL-EBI).

Why some patients with a rare but deadly leukemia fare much better than others

Dr. Jaeseung Kim and colleagues have identified three subtypes of BCR-ABL1 acute lymphoblastic leukemia that respond very differently to targeted treatment.

There’s more to a rare type of leukemia than once thought, and new discoveries by OICR-supported researchers could bring about more personalized approaches to treat it.

For decades, scientists have known that two types of leukemia are driven by the ‘BCR-ABL1’ gene: chronic myelogenous leukemia (CML) and a more acute disease called BCR-ABL1 acute lymphoblastic leukemia (B-ALL). This knowledge helped generate a group of targeted drugs called tyrosine kinase inhibitors (TKIs) which have been very effective at treating CML, with most patients able to live a normal lifespan.

But patients with BCR-ABL1 B-ALL have had dramatically different outcomes with the same treatment. TKIs work very well for some and have little effect on others. About half of patients diagnosed with this type of leukemia die within five years of diagnosis, and there has been no clear reason why.

Dr. Jaeseung Kim and Dr. Faiyaz Notta have found a potential explanation and published it in a recent Nature Genetics paper.

Kim, Notta and colleagues used RNA sequencing to study samples of BCR-ABL1 B-ALL from 53 patients treated at University Health Network (UHN) in Toronto, hoping to understand how the disease’s molecular makeup impacted patients’ clinical outcomes. From that work, they identified three distinct subtypes of the disease that differed in their biology and response to treatment.

At the biological level, the subtypes are defined by how ‘mature’ blood cells were when they transformed into cancer, ranging from an early stage of maturation (“Early-Pro”) to mid stage (“Inter-Pro”) to late progenitor (“Late-Pro”). For patients, these subtypes translate to significantly different responses to TKIs. People with Early-Pro subtype had very poor outcomes, with high rates of relapse and a five-year overall survival rate of 33 per cent. Whereas people with Late-Pro subtype had markedly positive responses to treatment, with five year-overall survival at 73 per cent.

“This was traditionally thought of as a single disease,” says Kim, who started this research as a member of Dr. John McPherson’s lab at OICR and Dr. Notta’s lab at UHN and has since become a Laboratory Genetics and Genomics Fellow at Harvard Medical School. “Our study shows there are actually huge differences within this disease, and knowing which subtype a patient has could potentially influence how they are treated.”

If the findings from the study can be replicated and confirmed, Kim says they could one day be used to develop a classification tool that tells patients which subtype they have. Then, patients whose subtype has a poorer prognosis could be given more aggressive treatment earlier, giving them a better chance at fighting the disease. Findings from the study could also be used to develop drugs that specifically target the subtypes.

“This study addresses a longstanding question about this disease and how it responds to TKIs, and presents exciting new opportunities for how to treat it,” says Notta, an OICR Associate and Co-Lead of the PanCuRx Translational Research Initiative.

For Kim, one of the most encouraging aspects of the study is how effective treatment was for patients with the Late-Pro subtype.

“They had spectacular response,” he says. “If we can bring the other subtypes up to that same level of response, patients will be in a much better situation.”

New funding partnership with U of T Data Sciences Institute aims to drive new breakthroughs

Partnering with University of Toronto’s Data Sciences Institute (DSI) will give OICR researchers access to new funding and collaborations.

OICR is combining forces with another Ontario leader in data science research to help leverage Big Data into new discoveries about cancer.

OICR will be partnering with the Data Sciences Institute (DSI), University of Toronto’s hub for data science research and training.

“Partnering with DSI is a natural step for OICR, which has been a leading data science institute since its inception and has made major contributions in cancer data sharing and analysis,” says Dr. Lincoln Stein, Head of Adaptive Oncology for OICR and Professor of Molecular Genetics at the University of Toronto.

The partnership will allow OICR investigators and students to apply for DSI-sponsored training grants, take part in educational and network opportunities, find new collaborative opportunities and share expertise with other members of the institute.

“We are very excited to have the Ontario Institute for Cancer Research join our growing DSI community,” DSI Director Lisa Strug said in an announcement about the partnership. “By connecting and supporting data science researchers, the DSI advances research and nurtures the next generation of data- and computationally focused researchers.”

DSI faculty includes experts in various disciplines, from environmental sciences to economics, and Stein says adding OICR into the mix increases the chances of making new and exciting discoveries together.

“The greatest breakthroughs in science have come when members from different scientific disciplines meet, compare notes, and have an aha! moment,” Stein says.

OICR’s President and Scientific Director says collaborations like these ensure OICR remains at the forefront of cancer research and care.

“With a shared commitment to maximizing the health and economic benefit of our research for the people of Ontario, this partnership with DSI holds tremendous potential to drive breakthroughs in cancer research that can bring real benefits to those affected by cancer,” says OICR President and Scientific Director, Dr. Laszlo Radvanyi.

OICR-led data resource deemed ‘critical’ to global biomedical research

The Reactome database was among 37 data resources to be recognized by the Global Biomedical Coalition.

A cutting-edge database of human cellular processes developed by OICR’s Dr. Lincoln Stein was named one of the world’s most indispensable biodata resources by an international coalition of research funders.

The Reactome database was one of just 37 data resources to make the Global Biomedical Coalition’s (GBC) inaugural Global Core Biodata Resources list, which recognizes databases that are “critical to life science and biomedical research worldwide.”

Founded in 2003 to drive innovations in biomedical research, Reactome is now the world’s largest open-access database of biological reactions and pathways. It is manually curated and includes advanced bioinformatics tools for researchers to interpret and analyze data.

Reactome is managed by Stein’s group in OICR’s Adaptive Oncology program along with teams at NYU Langone Health, the Oregon Health & Sciences University and the European Bioinformatics Institute. It is widely used among the research community, with a website that receives nearly 15 million visits per month.

“For many years now, Reactome has been an essential tool for interpreting genomic data and has led to many new insights into the causes and potential cures for human disease,” Stein says. “This recognition means that Reactome has passed a stringent selection process based on our stability, focus and research community size, and represents a strong endorsement by the world’s computational biology community.”

Researchers are increasingly relying on biodata resources to advance knowledge on how to how to prevent, detect and treat diseases like cancer, making it all the more important that these databases are easily accessible. All the resources on GBC’s list provide unrestricted access to researchers the world over.

Reactome is not the only of Stein’s projects to make the list. GBC also recognized the Alliance of Genome Resources, which harmonizes genomic and biological data from different model organisms, as contributed by its member organizations. Stein’s WormBase project, a model organism database for the roundworm (C. elegans), is one of the founding members of the alliance.

“Much of the world’s biological knowledge is locked away in PDFs which are inaccessible to the advanced computational algorithms needed to interpret large-scale datasets such as genomics,” Stein says. “Reactome and similar biodata resources unlock this knowledge and makes it available for computation, enabling the advancement of precision medicine, machine-aided diagnostic and drug discovery.”

How natural selection influences gene expression and can protect us from disease

An OICR study explored the molecular and population level forces driving allele-specific expression.

The genes we inherit from our parents determine many things about us, from our height and eye colour to our chances of getting diseases like cancer.

Each parent contributes equally, passing on one copy of each gene known as an allele. But the way those genes are expressed in our traits isn’t always equal.

That unequal expression of genes is known as allele-specific expression (ASE) and it can actually protect us from some of the harmful things coded into our DNA.

Michelle Harwood

University of Toronto PhD candidate Michelle Harwood recently led a study to find out what drives ASE, both at a molecular and a population level, using genetic data from the Canadian Partnership for Tomorrow’s Health (CanPath).

“We wanted to know whether ASE was occurring randomly or if there was a pattern,” says Harwood, who is based in Dr. Philip Awadalla’s lab at OICR.

The study results, published in Science Advances, provide new insights on how the forces of natural selection influence the expression of our genes, and could have implications for how we understand the risk and severity of diseases like cancer.

In its simplest terms, ASE is the over- or under-expression of one of the two alleles inherited from our parents. This can cause our phenotype (our physical traits) to be different than what would be expected from our genotype (our genetic makeup).

What makes ASE particularly interesting in a disease context is that it can cause harmful genetic mutations like the ones associated with cancer to be under-expressed. This in turn might cause a person to have less severe disease than someone with the exact same mutation.

This ‘protective’ phenomenon has already been documented in diseases like cancer, and Harwood and her colleagues wanted to know about the forces behind it.

They looked at the genomes of different population groups within the province of Quebec, including French Canadians with largely European ancestry, and recent immigrants with largely African heritage. They found that genetic diversity is an important driver of ASE, at both molecular and population levels.

Harwood and colleagues observed that parts of the genome with high levels of recombination — a natural re-shuffling of the alleles in a chromosome — had more ‘efficient’ ASE, meaning there was more under-expression of harmful mutations. This was similar to the patterns they observed across many different tissue types in data from the Genotype Tissue Expression (GTEx) consortium.

The size and diversity of a population were also important drivers. Individuals from older and more genetically diverse populations, like the African diaspora in Quebec, had more efficient ASE than the less-diverse French-Canadian population

“Over time, with more recombination, and in larger populations, there are more genetic combinations available for natural selection to act,” Harwood says. “While ASE can happen randomly, it’s natural selection that is causing it to be protective.”

Harwood and colleagues also looked at the influence of environmental factors on ASE. When comparing individuals with the same genetic ancestry but who live in a different geographic location of Quebec, they found differences in ASE in numerous genes. Although the specific environmental factors at play were not investigated, a 2018 study from the Awadalla lab suggests it could be due to different pollutant levels amongst Quebec subpopulations.

Though not covered in Harwood’s study, increasing our understanding of ASE and what causes it could have implications for cancer. Finding out a whether a cancer-driving mutation is over- or under-expressed in a particular person could potentially help predict their chances of severe disease.

The next step for Harwood is to explore the relationship between ASE and immunity, and whether ASE changes with immune response. Many genes identified in this current study were immune-related, so Harwood aims to explore these further at the single-cell level in blood.

She says that what she is learning about ASE and the factors behind it show just how immensely diverse humans are and how the mechanisms behind this diversity are complex but integral to our understanding of human evolution and disease progression.

“The world is so large and there are so many people out there, but yet we’re all so unique,” Harwood says.

Genome sequencing delivers real-time results for hard-to-treat pancreatic cancer

OICR’s PanCuRx program is unlocking the mysteries behind Canada’s fourth leading cause of cancer death and translating knowledge into better treatment options.

Tough to detect, quick to spread and stubbornly resistant to treatment, pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer.

Most people won’t have symptoms in the early stages, giving pancreatic tumours — which can metastasize when they’re no bigger than a fingernail — plenty of chance to spread. By the time PDAC is detected, it’s often too late for surgery. Fewer than one in 10 people will live five years past their diagnosis.

But advancements in genomic sequencing have opened a new window into what makes PDAC so challenging. OICR led a major push to study and catalogue molecular data about pancreatic cancer that is generating key insights on how best to treat it. And OICR’s unique Pancreatic Cancer Translational Research Initiative (PanCuRx) is turning those insights into real-world treatment decisions.

“The way we’re applying knowledge in real time is very cutting edge and hopefully it can offer a better path for people with pancreatic cancer,” says Dr. Steven Gallinger, a surgical oncologist and PanCuRx co-lead.

Gathering and translating sequencing data

OICR’s work on PDAC dates back to the early years of the Institute when the International Cancer Genome Consortium (ICGC) was first amassing genetic data about different forms of cancer. As one of the founding organizations behind ICGC, OICR contributed whole genomes and transcriptomes (WGTS) from early stage pancreatic tumours, helping build the world’s first high-quality data set of PDAC genomes.

The data generated by OICR fueled pancreatic cancer research around the world and led to the launch of PanCuRx, a multidisciplinary OICR program led by Gallinger and Associate Director Dr. Julie Wilson dedicated to understanding PDAC’s molecular biology and translating knowledge into tailored treatment strategies.

PanCuRx launched the landmark COMPASS clinical trial in 2015 in collaboration with a clinical team at University Health Network led by Dr. Jennifer Knox. COMPASS aimed to show that pancreatic tumours could be sequenced and analyzed in time to influence a patient’s second-line care (after surgery or chemotherapy), potentially pointing them to treatment options that targeted their tumour’s unique biology.

Dr. Steven Gallinger
Dr. Steven Gallinger

This ambitious trial was not without its challenges. PDAC tumours are notoriously aggressive, so tumours had to be sequenced and analyzed quickly in order to have any meaningful impact on the next phase of treatment. 

This was challenging because pancreatic tumours are difficult to sequence, both technically and logistically. Since the tumour biopsies were very small, with varying numbers of cancer cells, the PanCuRx team worked closely with UHN pathologist Dr. Sandra Fischer to implement a laser-capture microdissection technique to isolate and enrich the cancer cells which improved the quality of sequencing data. Multiple downstream steps were tightly coordinated so that the results could be discussed at a multidisciplinary ‘molecular tumour board’ to determine whether there were any molecularly guided treatment approaches that could benefit the patient.

Over five years and 270 participants, the trial successfully showed that genome sequencing could inform pancreatic cancer treatment decisions on a clinically relevant timeline. “That really made our mark in the world of translational research,” Gallinger says.

New insights to guide treatment

Proving feasibility was just one aspect of COMPASS. The sequencing and clinical data from the trial helped find clues about how PDAC responds to existing and potential treatment options.

For example, PanCuRx researchers identified four different subtypes of pancreatic cancer with distinct molecular properties that might be targeted by new therapies. They also found a rare mismatch repair (MMR) genetic signature that could make some pancreatic tumours more susceptible to immunotherapies.

One of the biggest discoveries was the GATA6 biomarker, which may be connected to how a pancreatic tumour responds to chemotherapy. GATA6 is still being validated as a biomarker through another clinical trial, but Gallinger says it is on the cusp on impacting treatment decisions. “It’s pretty convincing evidence,” Gallinger says. “If things go the way we expect, it could be influencing first-line care within a year.”

PanCuRx’s influence goes beyond its own trials. The huge amount of genomic data generated through the IGCG sequencing, COMPASS and subsequent trials is being harnessed by researchers around the world through the ICGC data sharing portal, the European Genome-Phenome Archive and other data repositories.

“I’m really happy to see our data shared widely and see so much good science is coming from it,” Gallinger says.

Driving collaborations across OICR

While collaboration with national and international scientists has been key to PanCuRx’s impact, some of the program’s most important connections are within OICR. “We’ve worked with colleagues in Diagnostic Development, Genomics, Informatics and all across the organization, and the teamwork has been amazing,” says Wilson.

Dr. Julie Wilson

She says OICR’s genomics lab has played a particularly important role in PanCuRx work. In many ways, the two programs have evolved alongside each other, with OICR’s genome sequencing capacity growing to meet the needs of programs like PanCuRx.

One of the biggest evolutions came in recent years, when OICR Genomics earned high-level accreditation from the College of American Pathologists (CAP) and Accreditations Canada. This means that OICR Genomics’ sequencing reports can be used clinically — not just for research purposes — in the U.S. and Canada, which helps PanCuRx sequencing meet the tight turnaround necessary to influence patient care. “PanCuRx and OICR Genomics have a very symbiotic relationship, and it has helped make our program a leader in the field,” Wilson says.

Taking the next step to support patients

Already at the forefront of translational pancreatic cancer research, the PanCuRx team is ready to take the next step toward improving patient outcomes with the launch of the Provincial Strategy for Personalized Management of Pancreatic Cancer (Prosper-PANC) trial in summer 2022.

Like COMPASS, Prosper-PANC will see PDAC patients have their tumour’s DNA and RNA sequenced in the hopes of identifying new and existing treatments that target their unique form of cancer. But it will focus on a younger cohort of patients than its predecessors, capturing patients under 60 who tend to have more actionable mutations.

Prosper-PANC will also investigate other exciting innovations in precision medicine, including whether blood biopsies can be used to sequence pancreatic tumours, and whether patient-derived organoids (PDOs) can help identify targeted treatment options.

PDOs are three-dimensional clusters of cells generated from a patient’s tumour cells. When a tiny drop of a cancer drugs is added to the organoid, it tends to respond the same way an actual tumour would respond to the drug. “The jury is still out on how useful PDOs are clinically,” Gallinger says. “But the early data shows they mimic response pretty well for the standard cancer drugs.”

If Prosper-PANC once again shows that sequencing pancreatic tumours can help improve treatment strategies, the PanCuRx team hopes their model can be rolled out more widely across Ontario. With the trial set to run in Toronto, Ottawa, Kingston, and London, Gallinger says there is potential to scale it up.

“A year from now, if the evidence is even more convincing that sequencing can improve patient outcomes, we will find a way to make it more accessible to people all across Ontario,” Gallinger says.

New precision diagnostics predict risk and response to breast cancer therapies

OICR’s Diagnostic Development program is taking two promising breast cancer tests from the lab to the clinic.

The ‘best’ treatments for breast cancer can vary dramatically from patient to patient. Different tumours respond differently to chemotherapies and targeted drugs, and finding the best treatment is about matching a patient’s specific form of cancer to the therapies with the best chance of stopping it.

This tailored approach to oncology is often called ‘precision medicine’ and it’s one of the core objectives of OICR’s Diagnostic Development program. “We develop tools to help understand each patient’s unique cancer so that they can receive the therapies they will benefit most from,” says Dr. Jane Bayani, Co-Director of Diagnostic Development at OICR.

But these tools don’t come easy. It takes a deep understanding of cancer’s underlying biology and a commitment to translating that understanding into clinically useful diagnostic tests.

Bayani and her fellow Co-Director Dr. Melanie Spears have spent nearly a decade developing two promising tests to predict how breast cancer patients will respond to treatment. Buoyed by collaborations across OICR, they have translated their innovations from the early days of biomarker discovery to the cusp of being adopted into the clinic, where they can help inform precision medicine decisions for the one in eight Canadian women who develop breast cancer.

Predicting risk of cancer recurrence

One test looks specifically at hormone receptor positive breast cancer, which accounts for at least 80 per cent of breast cancer diagnoses. For about half of patients, hormone therapy after surgery is enough to keep this type of breast cancer from recurring. But the other half will see cancer return within five to 10 years.

Dr. Jane Bayani

“A significant number will end up dying from the disease,” says Bayani, who has been exploring hormone receptor positive breast cancer since shortly after she joined OICR in 2012.

Back then, there weren’t many reliable ways to predict who might experience a recurrence during or after their initial treatment. This made it tough to determine which patients might benefit from additional drugs like chemotherapy, which could reduce their risk of recurrence.

With that in mind, Bayani and Dr. John Bartlett, who was OICR’s Director of Diagnostic Development at the time, set out to look for genetic clues. They identified a signature of 95 genes that seemed to correspond to breast cancer recurrence and developed a corresponding assay. Using a retrospective cohort study, they were able to validate that their 95-gene signature assay can better predict the risk of recurrence in hormone receptor positive breast cancer.

“Patients who are found to be at high risk of recurrence may want to consider chemotherapy, while those identified as low risk can just continue with hormone therapy,” Bayani explains.

But it’s not enough for the test to work in one of OICR’s labs. If this innovation is going to make an impact on patients, it needs to be reproducible at other labs around the world. Working with partners at OICR and external collaborators, Bayani worked to fine tune their discovery, and ultimately created a robust, reproducible assay and are in the process of confirming its clinical utility.

To date, their risk-stratifying test has been patented in Australia and Japan, with a provisional patent in the U.S. and patenting in progress in Canada, China, and Europe. Now, they are working with industry investors to find the best way to make the test widely available. “This is a Canadian discovery that could be disseminated locally, nationally and internationally,” Bayani says. “We’re looking forward to seeing it help patients get the most effective treatment.”

Knowing which cancer treatments work best

Anthracyclines are one of the most effective treatments for women with high-risk breast cancer. But they are also associated with serious side effects like heart failure and the potential to develop leukemia later in life.

Dr. Melanie Spears

“Because of these nasty side effects, we want to be sure that patients who are given anthracyclines will benefit from them,” Spears says.

This led Spears, Bartlett and their collaborators to explore ways to predict a patient’s response to anthracyclines. They worked with OICR’s Adaptive Oncology team to look for genes that were common in different samples of anthracycline-resistant tumours. Through that, they discovered that patients with low expression of histones H2A and H2B, two types of proteins found in DNA chromosomes, and other genes associated with the pathway were more likely to benefit from anthracycline treatment.

From that discovery, Spears, Bartlett and colleagues created what is believed to be the world’s first assay to predict response to anthracyclines and validated it in two separate clinical trials. “I see this assay being used at diagnosis to determine whether a patient should be receiving anthracyclines as part of their chemotherapy regime,” Spears says. “If it shows they won’t benefit from anthracyclines, they can be given a different regime and hopefully not have some of those severe side effects.”

With the test now fully patented the U.S., China, Europe and Canada, Spears and her team are currently exploring licensing options. Thanks to an investment from FACIT, they are also working to validate the test in a third clinical trial, hoping to achieve the highest standard of evidence.

“We want to get this innovation into the clinic,” Spears says. “We want to give clinicians all the evidence they need to be comfortable using the assay in their day-to-day practice.”

Moving toward personalized medicine

With both tests now in the commercialization phase, Spears and Bayani say it’s rewarding to see their projects move from an initial concept all the way toward clinical implementation.

Though the process took several years, they say it was helped by OICR’s commitment to translational research and the infrastructure it has built. “OICR over the past decade has really invested heavily in translational research. Now we’re seeing the fruits in that investment,” Bayani says.

If all goes to plan, OICR’s investment and the tools it is developing will enable a future where all Ontarians have access to diagnostics and treatments tailored to their unique needs.

In the case of the 95-gene signature test, Bayani and her colleagues are hoping to take the next step toward precision medicine.

Working with their industry partners, they are exploring how to link their risk-stratifying test with a targeted sequencing assay used to predict responses to targeted cancer therapies. With the combined knowledge from these two assays, breast cancer patients can be tested for their risk of recurrence, and high-risk patients can be directed to the additional therapies that give them the best chance of survival and quality of life.

“We want to bring that extra information to clinicians and their patients so they can better prioritize targeted treatments,” Bayani says. “That’s what the future of precision medicine is all about.”