By Billy Candra 
A groundbreaking collaborative effort spanning Canada has culminated in the development and successful application of an innovative method to rapidly identify personalized treatment strategies for young cancer patients. This pioneering approach involves cultivating patient-derived tumours within chicken eggs, serving as "avatars," and subsequently analyzing their intricate protein profiles—a technique known as proteomics—to pinpoint therapeutic vulnerabilities. The achievement, spearheaded by researchers from the University of British Columbia (UBC) and BC Children’s Hospital Research Institute (BCCHR), marks a significant milestone as the first instance in Canada where these two advanced techniques have been synergistically employed to identify and test a specific drug for a young patient’s aggressive tumour in a timeframe conducive to their ongoing treatment. This pivotal success, which saw the identification of a novel drug for a patient whose cancer had resisted conventional therapies, underscores the immense potential of proteomics as a crucial complement to established genomic analyses in the realm of real-time, individualized cancer care. The findings of this landmark study were formally published in the esteemed scientific journal EMBO Molecular Medicine, signalling a potential paradigm shift in how intractable pediatric cancers are approached.
The Pressing Challenge of Pediatric Cancer
Cancer remains a devastating diagnosis for children and adolescents globally, and specifically in Canada, it is the leading cause of death by disease among children. Approximately 1,000 Canadian children are diagnosed with cancer each year, with roughly 1 in 5,000 children under the age of 15 receiving such a diagnosis. While overall survival rates for many pediatric cancers have seen remarkable improvements over recent decades, largely due to advancements in chemotherapy, radiation, and surgery, a significant subset of these young patients face extremely poor prognoses. This includes individuals diagnosed with rare cancer types, those with aggressive forms of the disease, or patients whose cancers relapse and become resistant to standard-of-care treatments.
Unlike adult cancers, which are often linked to lifestyle factors and environmental exposures, pediatric cancers frequently arise from genetic mutations that occur early in development, making their biology distinct and often more challenging to treat. The conventional "one-size-fits-all" chemotherapy regimens, while effective for many, can also inflict severe short-term and long-term side effects on a child’s developing body, impacting their physical, cognitive, and emotional health for years, if not a lifetime. For the estimated 20% of young patients whose cancers do not respond to initial therapies or recur, treatment options quickly dwindle, and the search for effective alternatives becomes a race against time, often necessitating experimental approaches. This urgent need for rapid, personalized, and less toxic therapies forms the critical backdrop against which the UBC and BCCHR team’s breakthrough emerges.
PROFYLE and ACCESS: Fostering a Collaborative Ecosystem
The innovative research is a direct outcome of the collaborative spirit fostered by PROFYLE (PRecision Oncology For Young peopLE), a flagship initiative of the Canadian pediatric cancer network ACCESS (Advancing Childhood Cancer Experience, Science and Survivorship). These interwoven organizations represent a monumental, pan-Canadian commitment to improving outcomes for children and young adults grappling with cancer. PROFYLE, specifically, was established to bridge the gap between cutting-edge research and clinical application, ensuring that young patients across the country, particularly those with hard-to-treat or relapsed cancers, can benefit from the latest scientific discoveries.
Bringing together an expansive network of over 30 research and funding organizations, and uniting more than 100 investigators from diverse institutions across Canada, PROFYLE exemplifies the power of collective expertise. This collaborative model is particularly vital in the context of rare diseases like pediatric cancer, where individual institutions may lack the patient volume or specialized resources to conduct comprehensive research independently. By pooling resources, knowledge, and patient data, PROFYLE creates a robust infrastructure for accelerating discovery and translating it into tangible clinical benefits. ACCESS, as the broader network, provides the overarching framework for enhancing the entire childhood cancer experience, from diagnosis and treatment to survivorship, with a strong emphasis on integrating scientific advancements into patient care. The present study stands as a testament to the efficacy of this national collaborative ecosystem in addressing some of the most complex challenges in pediatric oncology.
A Patient’s Desperate Journey and the Turning Point
At the heart of this scientific triumph lies the compelling story of an unnamed young patient whose battle with a rare pediatric cancer proved exceptionally challenging. Diagnosed with a form of cancer that typically carries a guarded prognosis, the patient initially underwent standard chemotherapy protocols. However, the tumour exhibited an aggressive resistance, rendering these conventional treatments ineffective. In a desperate bid to identify alternative solutions, clinicians turned to genomics, the study of the patient’s genetic makeup and the tumour’s mutations, which has revolutionized cancer care by enabling the selection of targeted therapies. While genomics often provides crucial insights, in this particular case, it failed to yield any clear, actionable drug candidates after initial therapies had faltered and the tumour developed resistance to a genomics-guided drug. This left the clinical team in a precarious position, facing a rapidly progressing disease with no obvious therapeutic path forward.
It was at this critical juncture that the research team, led by senior investigators Dr. Philipp Lange, Dr. James Lim, and clinician Dr. Rebecca Deyell—all prominent figures within the Michael Cuccione Childhood Cancer Research Program at BCCHR—decided to pivot. Instead of succumbing to the limitations of genomics in this specific instance, they chose to explore an emerging frontier: proteomics. This decision underscored a profound commitment to patient care and an openness to innovative scientific exploration when conventional avenues had been exhausted. The study by co-lead authors Dr. Georgina Barnabas, a postdoctoral researcher in Dr. Lange’s lab, and Tariq Bhat, a PhD student in Dr. Lim’s lab, focused intently on this patient’s unique case, embodying the personalized medicine ethos.
Proteomics Unveiled: Beyond the Genetic Blueprint
The conventional understanding of cancer often begins with genomics, which examines the DNA sequence for mutations that drive tumour growth. While genes carry the instructions for life, dictating what proteins can be made, it is the proteins themselves that are the functional workhorses of our cells. Proteins are responsible for virtually every cellular process, from metabolism and signaling to structural support. Crucially, the vast majority of cancer drugs work by directly interacting with and modifying the activity of specific proteins.
"With genomics alone, we couldn’t find a clear treatment option for this patient," explained Dr. Lange. "But by looking at the tumour’s proteins, we found a critical metabolic weakness that we could target with an already approved drug." This statement succinctly encapsulates the rationale behind the team’s shift to proteomics. By analyzing the complete set of proteins expressed by the patient’s tumour—its "proteome"—the researchers aimed to uncover dynamic cellular activities and vulnerabilities that might not be evident from static genetic mutations alone.
Through sophisticated proteomic analysis, the team made a pivotal discovery: the patient’s tumour exhibited an unusually high reliance on an enzyme called SHMT2 (Serine Hydroxymethyltransferase 2). SHMT2 plays a crucial role in cellular metabolism, particularly in the one-carbon metabolism pathway, which is essential for nucleotide synthesis (building blocks of DNA and RNA) and amino acid metabolism, both vital for rapidly proliferating cancer cells. This heavy reliance on SHMT2 represented a metabolic Achilles’ heel. Armed with this knowledge, the researchers hypothesized that inhibiting SHMT2 could effectively "starve" the tumour by cutting off its access to a key energy source and essential building blocks for growth.
The strategy then shifted to finding a drug that could target SHMT2. A significant advantage of this approach was the potential for drug repurposing—identifying an existing, approved drug that could inhibit SHMT2. This bypasses years of costly and time-consuming drug development and clinical trials, as the drug’s safety profile is already established. The team identified sertraline, a common antidepressant, as a suitable candidate. Sertraline, while primarily known for its effects on serotonin reuptake, has been shown in preclinical studies to have off-target effects that include the inhibition of SHMT2. This offered a pragmatic and rapid pathway to clinical application.
The Avian Avatar: A Living Laboratory for Personalized Drug Testing
Identifying a potential drug candidate is only the first step; validating its efficacy against a patient’s specific tumour is paramount. Traditional preclinical models, such as cell lines or genetically engineered mouse models, often fail to accurately replicate the complex biology of individual human tumours, leading to high failure rates in clinical trials. Moreover, these models are often too slow to provide answers in the urgent context of rapidly progressing, resistant cancers.
To overcome these limitations, the UBC/BCCHR team employed a cutting-edge method involving the growth of a small piece of the patient’s tumour on a chicken egg. This innovative "avatar" model leverages the chorioallantoic membrane (CAM) of a developing chicken embryo. The CAM is a highly vascularized, immunodeficient membrane that provides an ideal environment for engrafting human tumour tissue. Once implanted, the patient’s tumour fragment can rapidly establish its own blood supply from the host embryo, mimicking the tumour’s growth dynamics and microenvironment within the patient.
"This technique speeds up the process of evaluating a treatment option in a way that simply wouldn’t be possible with traditional methods," stated Dr. Lim. "We could quickly confirm whether the drug we identified through proteomics could actually work for the patient’s tumour." The chicken egg avatar model offers several distinct advantages:
- Speed: Tumours can be engrafted and drug responses tested within weeks, significantly faster than the months typically required for patient-derived xenograft (PDX) mouse models.
- Cost-Effectiveness: Chicken embryos are considerably less expensive to maintain and work with compared to mammalian models.
- Personalization: The avatar is an exact replica of the patient’s tumour, preserving its unique genetic and proteomic characteristics, thereby ensuring highly personalized drug testing.
- Accessibility: The technique is relatively straightforward to implement in a well-equipped research laboratory, making it potentially more scalable.
These chicken egg avatars are a key component of the BRAvE initiative (Better Responses through Avatars and Evidence) at BCCHR. BRAvE serves as a vital bridge, connecting the clinical needs of patients with the innovative research capabilities of the hospital’s laboratories. It embodies the institutional commitment to translating scientific discovery into direct patient benefit, particularly for those facing the most challenging cancer diagnoses. The ability to grow an identical tumour outside the patient offered an unprecedented opportunity to test the identified drug (sertraline) directly on the patient’s own cancer in a controlled, rapid, and predictive manner.
Expert Consensus and Clinical Application
Following the successful identification of SHMT2 as a vulnerability and the promising preclinical validation of sertraline on the chicken egg avatar, the team presented their comprehensive findings to a panel of experts convened by PROFYLE. This multidisciplinary panel, comprising oncologists, pathologists, geneticists, and researchers from across Canada, meticulously reviewed the data. Their role is critical in evaluating the scientific rigor of the findings, assessing the potential benefits and risks, and ultimately making recommendations for clinical application, especially in cases where conventional treatments have failed.
After thorough deliberation, the PROFYLE expert panel reached a consensus: given the patient’s rapidly progressing, treatment-resistant cancer and the robust preclinical evidence, sertraline was deemed the most promising and viable treatment option available at that time. This endorsement provided the necessary clinical justification to proceed with administering sertraline to the patient, marking the culmination of the personalized precision oncology pipeline developed by the team.
Encouraging Results, A Glimmer of Hope, and the Road Ahead
The patient subsequently began treatment with sertraline. The clinical outcome, while not a complete cure, was highly encouraging. After initiating sertraline treatment, the patient’s tumour growth significantly slowed, arresting its aggressive progression. This vital intervention bought precious time for the patient and provided a much-needed reprieve from the relentless advance of the disease. In the context of a rare and resistant cancer where all other options had failed, even slowing tumour growth represents a profound clinical benefit, potentially extending life, improving quality of life, and opening windows for further treatment strategies.
"While there is more work to be done, this study shows that our approach can deliver personalized treatment recommendations fast enough to actually help patients with rare and difficult-to-treat cancers," emphasized Dr. Lange. The immediate impact on the patient underscores the clinical utility and timeliness of this integrated proteomics-and-avatar platform. However, the researchers acknowledge that the journey is far from over. The fact that the tumour growth slowed but did not entirely stop indicates that additional treatments or combination therapies will likely be necessary to achieve a more durable response or complete remission. This highlights the complex and adaptive nature of cancer, even when a critical vulnerability is targeted.
Looking to the future, the team’s immediate goal is to expand the application of this innovative method. "We now hope to expand this method to other children to identify effective treatments faster across the country," Dr. Lange articulated. Scaling up this approach involves several key steps:
- Broader Patient Cohort: Applying the technique to a larger number of pediatric cancer patients, particularly those with rare or relapsed diseases, to further validate its efficacy and identify new therapeutic targets.
- Systematic Implementation: Integrating the proteomics-and-avatar platform more routinely into the clinical decision-making process for hard-to-treat pediatric cancers across Canadian institutions.
- Further Research: Investigating combination therapies, understanding mechanisms of acquired resistance to targeted drugs like sertraline, and exploring new enzymes or pathways uncovered by proteomics.
- Technological Refinement: Continuously improving the speed, sensitivity, and throughput of both proteomic analyses and the chicken egg avatar model.
- Regulatory Pathways: Navigating the regulatory landscape for personalized, experimental treatments to ensure broader and more rapid access for patients.
This breakthrough represents a powerful testament to the potential of precision oncology, moving beyond the traditional trial-and-error approach to a more data-driven, individualized strategy. The integration of advanced proteomic analysis with rapid, patient-derived avatar models offers a beacon of hope for young patients and their families, promising a future where personalized treatment recommendations can be delivered with unprecedented speed and precision, ultimately improving outcomes for some of the most challenging forms of childhood cancer. The collaborative spirit of PROFYLE and ACCESS, coupled with the scientific ingenuity of institutions like UBC and BCCHR, is paving the way for a new era in pediatric cancer care.
