By Nana O 
A groundbreaking initiative spearheaded by a pan-Canadian research consortium has unveiled a novel, swift method for identifying personalized treatments for young cancer patients. This innovative approach involves cultivating patient-derived tumors within chicken eggs and subsequently analyzing their protein profiles to pinpoint effective therapeutic strategies. This pioneering work, detailed today in the esteemed journal EMBO Molecular Medicine, marks a significant advancement in the fight against pediatric cancers, particularly those that prove resistant to conventional therapies.
The PROFYLE Initiative: A Collaborative Leap in Pediatric Oncology
The research team, a collaborative effort primarily driven by scientists from the University of British Columbia (UBC) and the BC Children’s Hospital Research Institute (BCCHR), is the first in Canada to successfully integrate tumor growth in an avian model with advanced proteomic analysis to expedite drug identification for a pediatric patient. This achievement underscores the immense potential of proteomics, the study of proteins, as a vital complement to genomics, the study of genes, in the real-time management of cancer.
This transformative project is a flagship component of PROFYLE (PRecision Oncology For Young peopLE), a crucial initiative under the umbrella of ACCESS (Advancing Childhood Cancer Experience, Science and Survivorship), Canada’s national pediatric cancer network. ACCESS unites over 30 research and funding organizations and more than 100 investigators from across the nation, all dedicated to enhancing cancer outcomes for children and young adults. The collaborative spirit of PROFYLE has been instrumental in pooling expertise and resources to tackle complex challenges in pediatric oncology.
Unveiling Hidden Vulnerabilities: The Power of Proteomics
The study, co-led by Dr. Georgina Barnabas, a postdoctoral researcher in the laboratory of Dr. Philipp Lange, and Tariq Bhat, a PhD student in Dr. James Lim’s lab, focused on a young, unnamed patient battling a rare pediatric cancer that had shown remarkable resistance to standard treatment protocols. Traditional therapeutic avenues, including chemotherapy and targeted drugs identified through genomic sequencing, had unfortunately proven ineffective, leaving the medical team with limited options.
Genomic testing, while a powerful tool, provides a blueprint of the genetic instructions within cancer cells. However, it is the proteins, the functional workhorses of the cell, that execute these instructions and are the direct targets of most cancer drugs. Recognizing this, the research team hypothesized that a deeper dive into the tumor’s proteome—its complete set of proteins—could reveal vulnerabilities that genetic analysis might overlook.
"With genomics alone, we couldn’t find a clear treatment option," stated Dr. Philipp Lange, a senior investigator with the Michael Cuccione Childhood Cancer Research Program at BCCHR. "But by looking at the tumor’s proteins, we found a critical metabolic weakness that we could target with an already approved drug."
The proteomic analysis of the patient’s tumor revealed an unexpected dependency on a specific enzyme, SHMT2 (serine hydroxymethyltransferase 2). This enzyme plays a critical role in the tumor’s metabolic pathways, providing essential building blocks for its rapid growth and proliferation. While genomic sequencing had not flagged this as a primary target, the proteomic data highlighted SHMT2 as a significant vulnerability.
The Chicken Egg Avatar: A Miniature Cancer Sandbox
To test the hypothesis that inhibiting SHMT2 could halt tumor growth, the researchers employed a revolutionary ex vivo (outside the body) model: the chicken egg. This method, a cornerstone of the BRAvE (Better Responses through Avatars and Evidence) initiative at BCCHR, involves implanting a small sample of the patient’s tumor into a fertilized chicken egg. The egg’s internal environment provides a nurturing ground for the tumor cells to grow and proliferate, creating an "avatar" that mirrors the patient’s own cancer.
This avatar model offers a critical advantage: it allows for the rapid testing of various drug responses in a controlled environment, significantly accelerating the timeline for treatment selection. Traditional methods of drug testing can take months, often far too long for critically ill pediatric patients. The chicken egg avatar, however, can be cultivated and tested within a matter of weeks.
"This technique speeds up the process of evaluating a treatment option in a way that simply wouldn’t be possible with traditional methods," explained Dr. James Lim, another senior investigator with the Michael Cuccione Childhood Cancer Research Program at BCCHR. "We could quickly confirm whether the drug we identified through proteomics could actually work for the patient’s tumour."
Repurposing an Antidepressant: An Unexpected Therapeutic Agent
The identified dependence on SHMT2 led the researchers to explore existing drugs that could inhibit this enzyme. Their investigation pointed towards sertraline, a widely prescribed antidepressant commonly known by brand names such as Zoloft. Sertraline has been shown in preclinical studies to inhibit SHMT2, thereby disrupting the tumor’s energy supply and potentially halting its growth.
The strategy was elegant in its simplicity: to use a readily available and well-understood medication to target a newly identified critical pathway in the aggressive pediatric cancer. This approach aligns with the principles of drug repurposing, which seeks to find new uses for existing medications, often leading to faster approval pathways and reduced development costs.
A Collaborative Decision and Promising, Yet Incomplete, Results
Once the proteomic analysis identified SHMT2 as a target and sertraline as a potential inhibitor, the research team presented their findings to a panel of experts established by PROFYLE. This multidisciplinary panel, comprising oncologists, researchers, and drug development specialists, meticulously reviewed the evidence. Based on the compelling data from the proteomic analysis and the chicken egg avatar experiments, sertraline was deemed the most promising treatment option for the patient at that critical juncture.
The patient was subsequently initiated on sertraline treatment. The initial results were encouraging, demonstrating a significant slowdown in tumor growth. However, the treatment did not achieve a complete remission, indicating that while sertraline offered a valuable therapeutic intervention, it was not a standalone cure. This outcome highlights the complex and often heterogeneous nature of cancer, even within a single patient.
"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," Dr. Lange emphasized. "We now hope to expand this method to other children to identify effective treatments faster across the country."
Broader Implications and Future Directions
The success of this pan-Canadian collaboration has profound implications for the future of pediatric cancer treatment. It demonstrates the power of integrating advanced proteomic analysis with sophisticated ex vivo tumor models to overcome the limitations of traditional diagnostic and therapeutic approaches.
Supporting Data and Context:
- Incidence of Rare Pediatric Cancers: Rare pediatric cancers, by definition, occur infrequently, making it challenging to conduct large-scale clinical trials for each specific subtype. The International Agency for Research on Cancer (IARC) estimates that childhood cancer accounts for approximately 1 in 200 cancers diagnosed worldwide. Rare cancers represent a significant portion of these diagnoses.
- Genomics vs. Proteomics in Cancer: While genomics has revolutionized cancer research by identifying genetic mutations driving cancer, it may not always reveal the complete picture. Proteins are the direct effectors of cellular function, and their abundance, modification, and interactions can change dynamically, influencing drug response in ways not always predicted by gene sequences alone. Studies have shown that the proteome can differ significantly from the transcriptome (RNA levels), emphasizing the need for proteomic insights.
- Drug Repurposing Success Rates: Drug repurposing has a proven track record in various fields of medicine. For instance, thalidomide, initially withdrawn due to severe birth defects, was later repurposed for treating multiple myeloma. The advantage lies in the established safety profiles of existing drugs, potentially shortening the path to clinical application.
Timeline of Key Events (Inferred):
- Diagnosis: Patient diagnosed with a rare pediatric cancer.
- Initial Treatments: Conventional chemotherapy and drug therapies are administered.
- Treatment Resistance: Tumour demonstrates resistance to initial treatments.
- Genomic Analysis: Genetic sequencing is performed, but no clear drug targets emerge.
- Proteomic Analysis: The research team undertakes proteomic analysis of the tumour.
- SHMT2 Identification: Proteomics reveals a critical dependency on the SHMT2 enzyme.
- Chicken Egg Avatar Creation: A sample of the patient’s tumour is grown in a chicken egg.
- Drug Screening: Sertraline is tested on the tumour avatar for its ability to inhibit SHMT2.
- Expert Panel Review: PROFYLE expert panel reviews the findings and recommends sertraline.
- Patient Treatment Initiation: Patient begins treatment with sertraline.
- Outcome Assessment: Tumour growth slows, but further treatment is required.
- Publication: Study results published in EMBO Molecular Medicine.
The BRAvE initiative’s integration of clinical care with cutting-edge research facilities at BCCHR is crucial for translating laboratory discoveries into tangible patient benefits. The PROFYLE network’s ability to convene experts from across Canada ensures that promising findings are rigorously evaluated and disseminated, fostering a national approach to tackling childhood cancer.
While this specific case involved a single patient, the methodology holds the potential to benefit countless others. The prospect of rapidly identifying personalized treatment strategies, especially for children with relapsed or refractory cancers, offers a beacon of hope. This research signifies a paradigm shift, moving towards a more precise, protein-centric approach to cancer therapy, where the unique molecular landscape of each tumor is systematically explored to guide treatment decisions. The ongoing efforts to expand this method to a wider patient population will undoubtedly be closely watched by the global oncology community.
