Periodic Reporting for period 1 - Maxima Butterfly (From Caterpillar to BUTTERFLY: supporting transformation of DCs in a paediatric oncology network)
Reporting period: 2023-01-01 to 2024-12-31
The Máxima Butterfly programme is an innovative initiative aimed at cultivating the next generation of pediatric oncology scientists. The project represents a unique and comprehensive training program, offering 28 international PhD students unparalleled opportunities for growth and impact. This robust research program spans the entire spectrum of pediatric oncology: from fundamental research to expose genetic and molecular characteristics of tumor cells to translational experiments to develop personalized therapy, leading to clinical trials to test novel and improved treatment options. Every avenue is explored in pursuit of improved outcomes and enhanced quality of life for young patients and their families. Additionally, collaborations are fostered both within and outside the center, resulting in partnerships with esteemed institutions worldwide to accelerate progress in the fight against pediatric cancer. Each student in the Máxima Butterfly project will focus their research on one of five areas: Brain Tumors, Solid Tumors, Blood Cancers, New Technologies, and Quality of Life. They will receive training in the basic aspects of pediatric cancer treatment and skills that can be applied across different fields (such as intellectual property, sharing knowledge, and entrepreneurship).
Moreover, the programme fosters interaction with academic, clinical, and entrepreneurial experts through specialist training, networking activities, and participation in summer and winter schools. These (inter)national connections provide students with the chance to collaborate with esteemed academic, industrial, and patient advocacy groups. This multidisciplinary approach not only enriches the experiences of the Máxima Butterfly Doctoral Candidates (DCs) but also cultivates a collaborative environment conducive to breakthrough discoveries and advancements in pediatric cancer research. Being embedded within Utrecht University, a leading international research institution, provides the Máxima Butterfly DCs access to state-of-the-art educational resources and graduate schools.
The insights gained from the research carried out within the program will advance our understanding of both pediatric oncology and the broader field of cancer research. Impressively, although at the very early stages of this project, there has been one open-access publication with 12 more in the pipeline. Efforts to connect with stakeholders and generate interest among external stakeholders, including the broader community, have led to numerous impactful activities such as courses, workshops, participation in the Weekend of Science (Utrecht Science Park), school outreach programs, and even lighthearted pub events. Notably, the Dutch Enterprise Agency, part of the Ministry of Economic Affairs, recently boosted the Butterfly program by promoting it through their social media channels. This collaboration has been vital in raising awareness of the Butterfly project among RVO stakeholders, significantly broadening its reach both nationally and internationally. A significant moment for the Butterfly management team during the first period was the video message from European Commission President Ursula von der Leyen in November 2023, expressing the European Union's strong support for the project.
Additionally, to maximize societal impact, milestones and activities are posted on the designated Maxima Butterfly website and social media channels. Project results are promoted through outreach activities such as posters and guest speaker appearances at (inter)national scientific research conferences. Furthermore, the Máxima Butterfly maximizes its visibility through posts on the established Princess Máxima Center’s website and LinkedIn platforms. The Center boasts 41K LinkedIn followers, and the Care and Research section of the Princess Máxima Center’s website publishes articles at strategic intervals throughout the year. The latest article showcased Butterfly PhD student Mianyong Ding as one of twelve pediatric radiotherapists from nine European countries who learned how artificial intelligence can help in the irradiation of children with kidney tumors.
Overall, the Maxima Butterfly program's expected impacts are significant, encompassing advancements in pediatric cancer research, fostering international collaboration, training the next generation of scientists and clinicians, and contributing to global efforts to improve outcomes for children with cancer. Economically, immunotherapy developments will create new markets for pharmaceutical companies. This helps drive significant investment in research and development of targeted cancer treatments. Improved long-term side effect management can significantly reduce long-term healthcare costs. Liquid biopsies for detecting residual cancer cells demonstrate a cost-effective alternative to traditional invasive diagnostic procedures, potentially reducing healthcare expenditures by reducing the number of unnecessary surgeries and extensive testing.
All of these research activities drive interdisciplinary collaborations, which promote technological innovation. Treatment standardization is improved, which can also result in accelerated regulatory approval and clinical implementation.
On a societal level, developments that improve the children’s overall quality of life will potentially reduce family and caregivers’ stress. Early neuropsychological screening enables more proactive and personalized healthcare interventions. These early interventions can potentially reduce developmental challenges for children.
Through the Butterly project, worldwide collaborations are established, and researchers gain valuable insight into potential disease biomarkers that can ultimately be used for detection, treatment, and, in some cases, disease prevention. We are only at the beginning of this exciting journey, and we expect further scientific developments during the course of this project. The results of this initiative will extend far beyond the lifetime of the Máxima Butterfly project.
To support the successful delivery of the Máxima Butterfly project and its objectives, guidance from the management committee in the form of regular meetings is essential. Moreover, the Máxima Butterfly SAB includes distinguished oncology researchers hailing from five prestigious academic centers: 1) KiTZ Heidelberg. Germany; 2) Tel Aviv University, Israel 3) Institute Curie Paris, France; 4) University of Toronto, Canada; and 5) Astra Zeneca, UK. The reviewers were selected for their expertise in the five pillars of the Máxima Butterfly programme: 1) Brain Tumours, 2) Haematology malignancies, 3) Solid Tumours, 4) Quality of Life, and 5) New Technologies. The advisory board members ensure the project's scientific excellence through their oversight. The annual virtual meetings serve as a platform to review progress and offer guidance. This helps mitigate risks and ensures the primary objectives of this comprehensive and ambitious training programme are followed, namely:
• Increase knowledge in the global field of pediatric cancer biology.
• Enhance international collaborations and European Pediatric Networks.
• Foster knowledge transfer and collaborations with industry.
• Facilitate the translation of preclinical research into clinical trials.
The comprehensive evaluation and selection process resulted in the hiring of 28 international candidates within a six-month recruitment timeframe. To ensure a fair and impartial selection process, the anonymity of the applicants was strictly maintained. Candidates were asked to apply using the CV template provided on the Máxima Butterfly website, and clear guidelines were provided on the application page regarding adherence to the anonymity regulations. The recruitment process involved internal and external reviewers. This thorough and systematic process, although time-consuming, ensured fairness and was primarily focused on delivering strict impartiality. All candidates had successfully started their positions by October 1st, 2023.
Although in the early stages of this project, there have been numerous scientific developments that have led to innovative advancements in paediatric oncology research. These include treatments involved in offering new hope for more precise and compassionate treatment approaches. Researchers have developed groundbreaking technologies that promise to transform diagnosis and treatment of childhood cancers, particularly brain tumors and neuroblastoma.
Key innovations include:
• A cutting-edge liquid biopsy test that can more accurately detect and track cancer cell mutations.
• Advanced precision diagnostics to refine treatment strategies.
• Targeted immunotherapy interventions designed to improve treatment effectiveness.
• Innovative approaches to minimize treatment side effects, such as developing strategies to protect children's hearing during cancer treatment.
Impressively, although at the very early stages of this project, there has been one open-access publication with 11 more in the pipeline. Student Leonor de Souza Teles’s publication highlights the important role of PET-based (Positron emission tomography) molecular imaging in improving the assessment and management of solid tumors in children (https://doi.org/10.1016/j.ejcped.2024.100203(opens in new window)). Student Amirhossein Masroor’s manuscript has been accepted for publication. This review revealed that while half of the children receiving cisplatin chemotherapy developed hearing damage, giving sodium thiosulfate (STS) through the bloodstream can help protect their hearing. Although lab studies suggested that applying STS directly to the ear might also help, this hasn't proven effective in patients. Therefore, doctors currently don't recommend using STS ear treatments for children with cancer. These findings underscore the importance of minimizing the long-term and sometimes chronic side effects of cancer treatments in children. Research is urgently needed to develop more targeted, less toxic therapies. Research is urgently needed to develop more targeted, less toxic therapies. It is expected that future open-access publications will attract the interest of researchers and stakeholders.
Furthermore, industry partnerships have been further expanded and strengthened. A significant highlight of this progress was the awarding of the Genmab Jan van Zwinkel subsidy to one of the students. This accomplishment is more than just an individual success; it represents a promising connection for future fellows and signifies the project’s growing industry connections. The industrial market fair embedded in the Autumn training school attracted multinational companies such as Genmab, Sanofi, Roche, Crown Bioscience, Ambagon Therapeutics, and the European Medicines Agency. This helped to provide students with comprehensive industry perspectives but also served to foster and strengthen industrial connections.
Moreover, industrial ties were further strengthened at the autumn training school (23 – 25 September) entitled “European Networks - Bridging the Gap Between Academia and Industry.” The autumn school was jointly organized by the Vagabond (ITN) and the Máxima Butterfly projects, bringing together 43 PhD students working in the pediatric cancer field. This training school allowed the 28 first-year Butterfly PhDs to share experiences with the 15 final-year Vagabond PhD students who brought diverse perspectives from 11 different oncology institutes across Europe. These interactions proved incredibly valuable, offering first-year students insights into advanced research experiences and practical industry perspectives. By facilitating direct communication between emerging researchers and experienced professionals, the training school exemplified an effective approach to bridging academic learning and real-world scientific practice.
Significantly, the Autumn training school featured an engaging industrial market fair that offered participants a unique opportunity to explore potential career paths. Multinational companies like Genmab, Sanofi, Roche, Crown Bioscience, Ambagon Therapeutics, and the European Medicines Agency participated, providing students with comprehensive industry perspectives. There was a dedicated speed-dating session for the Máxima Butterfly and Vagabond students that facilitated meaningful discussions, and the Butterfly students benefited from exploring potential secondment opportunities. The Butterfly and Vagabond students were given opportunities to showcase their research through selected speaker presentations and poster sessions. Beyond scientific knowledge, the training school emphasized personal journeys that demonstrated how different experiences contribute to professional growth and character building. Similar to the autumn school held from 30 October to 02 November 2023, the training schools remain open to all research members at the Princess Máxima Center, creating an environment that encourages participation and collaboration.
The training schools go beyond technical education, fostering valuable transferable skills in data management, ethical responsibilities, and sustainability practices. Moreover, each student is developing a green lab management plan, demonstrating their commitment to sustainability. In addition, to enhance their communication abilities, students write engaging articles for a general audience after each autumn school, which are available on the Butterfly news webpage.
For the upcoming school, which is planned for the first quarter of 2025, five of the Butterfly students are members of the organization team together with the project manager. Students Miguel Martins, Jessica Beamish, Elizaveta Kulaeva, Julie Wijns, and Maria Leonora de Sousa Teles represent each of the five Butterfly research pillars, Haematoloy malignancies, Quality of Life, New technologies, Brain tumours, and Solid tumours, respectively. The students will develop essential skills, including putting the programme together, inviting key speakers, logistics management, administrative skills, communication, and post-event tasks such as collecting feedback questionnaires and managing invoices as well as post-conference materials.
Embedded within the training schools is the comprehensive personal development programme, which is shaping our students into confident, resilient leaders of tomorrow. So far, students have participated in three personal development sessions. These sessions include one-day as well as overnight retreats. They take place in the serene woodland surroundings of De Hoorneboeg, Hilversum, The Netherlands, providing a peaceful retreat from their work environment.
Considering many of the students have just over one year of employment, they are making excellent progress:
• Four students have already completed their first secondment.
• One student’s nine-month secondment is ongoing. Her remaining six-months will be completed in June 2025.
• The remaining students are actively planning their upcoming placements.
This proactive approach demonstrates our students' enthusiasm and the programme's commitment to providing diverse, real-world experiences in paediatric oncology research.
Some of the key results and their clinical relevance include the following:
• Development of a multi-organ auto-segmentation model suitable for various organs at risk, which can be applied to multiple datasets in clinical settings. This means improving efficiency and reducing the inter-observer variability in radiotherapy treatment planning effects for young patients.
• Improved therapy techniques using VMAT, which has excellent locoregional control. This means improved locoregional control of treatment.
o More precise radiation targeting
o Reduced radiation exposure to healthy tissue
o Improved dosage delivery to tumor sites
Volumetric Modulated Arc Therapy (VMAT) is an advanced radiation therapy technique used in cancer treatment. In VMAT, radiation beams are delivered continuously as the treatment machine rotates around the patient.
The key advantage of VMAT is its ability to shape radiation beams more conformally around tumor volumes while minimizing damage to surrounding healthy tissue.
• Developments in enhanced precision in radiation delivery will potentially lead to a reduction in radiation exposure to healthy tissue.
• Exploring ways for children to receive effective cancer treatment while preventing the unwanted side effects of loss of hearing is making progress. An open-access review with contributions from Butterfly student Amir Masroor will be published in 2025. “Local application of sodium thiosulfate as an otoprotectant for cisplatin-exposed patients – A narrative literature review to explore the potential benefit for children with cancer.”
• Thymic peptides have the potential to improve clinical outcomes. The peptides enhance recovery and reduce complications in post-HCT (Hematocrit) patients, which allows for a potential therapeutic role in immune recovery patients.
• Age and stromal cells influence hematopoiesis. Developments in this field of research facilitate Insights into pediatric blood disorders. This will be the 1st comprehensive paediatric healthy reference published dataset that researchers can use.
• Developments in therapeutic drug monitoring (TDM) optimize drug delivery and reduce toxicity risk. This will potentially lead to the dosage adjustment of components of ALL treatment to improve outcomes and efficacy of treatment in childhood cancer.
• Identification of novel biomarkers for both highly functional and ineffective T cells, that could be exploited to enhance the therapeutic efficacy of Immunotherapies. This means BGT has the potential to drive innovations in personalized immunotherapeutic strategies, with the ultimate goal of improving patient outcomes of cancer treatment.
• Blinatumomab added to the Interfant-06 chemotherapy continued to show a high level of efficacy in infants with KMT2A-rearranged ALL. Studies have shown that pharmacokinetic properties were stable across age categories, corroborating dose efficacy. This means the remarkable efficacy and safety of Blinatumomab combined with chemotherapy have now been introduced as frontline therapy in the Interfant-21 clinical protocol/trial.
• A comprehensive list of barriers and facilitators. This means Implications for implementation toolkits when implementing psychosocial screening.
• Male and female caregivers have different curves of distress. The predictors that contribute to stress are parent-related. This allows for new interventions to be improved and tailored based on the predictors and gender.
The students are making steady progress through ongoing research to advance these developments. We expect the findings to be shared through open-access journals and presented at various academic events, including conferences, symposia, and annual meetings.
Further impressive outputs since the start of the project have resulted in the open-access publication of one manuscript, one review article has been accepted for publication, and 10 more publications are in the pipeline. Amir Masroor contributed to a review article to be published in 2025 titled “Local application of sodium thiosulfate as an otoprotectant for cisplatin-exposed patients – A narrative literature review to explore the potential benefit for children with cancer.” Student Leonor Teles’ first author publication, “Potential of non-FDG PET radiotracers for paediatric patients with solid tumours” (https://doi.org/10.1016/j.ejcped.2024.100203(opens in new window)) investigated molecular imaging using specialized Positron emission tomography (PET) and fluorodeoxyglucose (FDG) tracers. These tracers show significant potential for improving diagnostic accuracy, staging, and treatment monitoring. However, advanced PET tracers require more comprehensive, long-term prospective studies to establish their clinical impact on pediatric oncology patient management and prognosis.