Periodic Reporting for period 2 - VAGABOND (Validation of Actionable Genomic ABerrations in a paediatric Oncology Network for Doctorate students)
Reporting period: 2022-12-01 to 2024-11-30
Pre-clinical drug development for pediatric cancers is highly complex, resource-intensive, and requires multidisciplinary expertise alongside innovative approaches. The VAGABOND-ETN consortium, consisting of 12 academic and 6 non-academic partners across 8 European countries, has trained 15 Early-Stage Researchers (ESRs) to address these challenges.
The overall aim of VAGABOND is to establish a multidisciplinary and multi-sectoral framework to efficiently validate new target-drug combinations in pediatric cancers. This is achieved through three main scientific objectives:
1. Identification and validation of pediatric cancer-specific molecular genetic aberrations and related interventions.
2. Characterization of epigenetic changes in pediatric cancers and their translation into targeted therapies.
3. Analysis of the immune environment in pediatric cancers and the development of therapeutic immune interventions.
Scientific and Societal Impact
VAGABOND directly addresses key challenges in pediatric cancer research, aiming to bridge knowledge gaps and accelerate drug development. The anticipated impact includes:
Advancing knowledge in eight difficult-to-treat pediatric cancers by overcoming challenges related to their rarity through data-sharing and collaboration.
Enhancing expertise in the proof-of-concept pipeline for preclinical drug development, focusing on genetic, epigenetic, and immunologic targets.
Training a new generation of scientists with the skills to translate scientific discoveries into therapeutic applications, fostering innovation and entrepreneurship.
Through international education and multidisciplinary collaboration, the consortium provided a unique European training network, equipping ESRs with comprehensive expertise in preclinical drug development. Researchers gained access to leading academic research groups, specialized multi-sectoral companies, and cutting-edge technologies, strengthening their ability to address future challenges in translational medicine.
The overall aim of VAGABOND is to establish a multidisciplinary and multi-sectoral framework to efficiently validate new target-drug combinations in pediatric cancers. This is achieved through three main scientific objectives:
1. Identification and validation of pediatric cancer-specific molecular genetic aberrations and related interventions.
2. Characterization of epigenetic changes in pediatric cancers and their translation into targeted therapies.
3. Analysis of the immune environment in pediatric cancers and the development of therapeutic immune interventions.
Scientific and Societal Impact
VAGABOND directly addresses key challenges in pediatric cancer research, aiming to bridge knowledge gaps and accelerate drug development. The anticipated impact includes:
Advancing knowledge in eight difficult-to-treat pediatric cancers by overcoming challenges related to their rarity through data-sharing and collaboration.
Enhancing expertise in the proof-of-concept pipeline for preclinical drug development, focusing on genetic, epigenetic, and immunologic targets.
Training a new generation of scientists with the skills to translate scientific discoveries into therapeutic applications, fostering innovation and entrepreneurship.
Through international education and multidisciplinary collaboration, the consortium provided a unique European training network, equipping ESRs with comprehensive expertise in preclinical drug development. Researchers gained access to leading academic research groups, specialized multi-sectoral companies, and cutting-edge technologies, strengthening their ability to address future challenges in translational medicine.
Scientific Achievements and Conclusions
The VAGABOND consortium successfully identified and validated genetic aberrations across multiple pediatric cancers. Key findings include:
Genetic Aberrations and Target Validation
- Precursor B-Cell Leukemia and Lymphoma: Genetic aberrations linked to immune suppression and therapeutic resistance, particularly focusing on T-cell function in the leukemic microenvironment.
- Pediatric Brain Tumors: Epigenetic changes regulated by BRD4 and the Polycomb complex (EZH2) as potential therapeutic targets.
- Therapy-Resistant Neuroblastoma: Investigated extracellular matrix signaling pathways, highlighting the roles of cancer-associated fibroblasts and tumor-associated macrophages.
- ATRX-Deficient Hepatoblastoma: Identified vulnerabilities linked to ATRX mutations, affecting proliferation and DNA repair pathways.
- Neuroblastoma: Discovered CDK12 as a therapeutic target, enabling combination therapies exploiting the BRCAness phenotype.
Epigenetic Research and Translational Applications
- Defined tumor-specific epigenetic mechanisms in various pediatric cancers, enabling targeted therapy development.
- Developed CRISPR-based screening methods to identify epigenetic vulnerabilities.
- Studied the impact of histone modifications on tumor progression and resistance.
Immune System Targeting and Immunotherapy Innovations
- Developed a comprehensive single-cell atlas of the neuroblastoma immune environment, identifying key immunosuppressive mechanisms.
- Demonstrated the therapeutic potential of anti-TIGIT/PD-L1 blockade in chemotherapy-resistant neuroblastoma models, highlighting its potential for future clinical trials.
- Developed dual-target CAR-T and TCR therapies to improve immune recognition and resilience against pediatric tumors.
The VAGABOND consortium successfully identified and validated genetic aberrations across multiple pediatric cancers. Key findings include:
Genetic Aberrations and Target Validation
- Precursor B-Cell Leukemia and Lymphoma: Genetic aberrations linked to immune suppression and therapeutic resistance, particularly focusing on T-cell function in the leukemic microenvironment.
- Pediatric Brain Tumors: Epigenetic changes regulated by BRD4 and the Polycomb complex (EZH2) as potential therapeutic targets.
- Therapy-Resistant Neuroblastoma: Investigated extracellular matrix signaling pathways, highlighting the roles of cancer-associated fibroblasts and tumor-associated macrophages.
- ATRX-Deficient Hepatoblastoma: Identified vulnerabilities linked to ATRX mutations, affecting proliferation and DNA repair pathways.
- Neuroblastoma: Discovered CDK12 as a therapeutic target, enabling combination therapies exploiting the BRCAness phenotype.
Epigenetic Research and Translational Applications
- Defined tumor-specific epigenetic mechanisms in various pediatric cancers, enabling targeted therapy development.
- Developed CRISPR-based screening methods to identify epigenetic vulnerabilities.
- Studied the impact of histone modifications on tumor progression and resistance.
Immune System Targeting and Immunotherapy Innovations
- Developed a comprehensive single-cell atlas of the neuroblastoma immune environment, identifying key immunosuppressive mechanisms.
- Demonstrated the therapeutic potential of anti-TIGIT/PD-L1 blockade in chemotherapy-resistant neuroblastoma models, highlighting its potential for future clinical trials.
- Developed dual-target CAR-T and TCR therapies to improve immune recognition and resilience against pediatric tumors.
Progress Beyond the State of the Art
VAGABOND has significantly advanced pediatric cancer research by:
Identifying and validating novel therapeutic targets across eight difficult-to-treat pediatric cancers.
Developing innovative preclinical models, including 3D tumor cultures and single-cell transcriptomics.
Pioneering novel immunotherapy strategies, such as dual-target CAR-T and TCR therapies, to enhance treatment efficacy and overcome tumor resistance.
Enhancing liquid biopsy approaches, enabling non-invasive monitoring of chemotherapy resistance and paving the way for personalized treatment strategies.
Expected Results Until the End of the Project
By the conclusion of VAGABOND, the project aims to:
✅ Refine and validate preclinical models to facilitate the transition of promising therapies into clinical testing.
✅ Strengthen interdisciplinary collaborations between academia, industry, and hospitals to accelerate drug development.
✅ Disseminate findings through high-impact publications, scientific conferences, and engagement with regulatory bodies.
✅ Equip ESRs with critical expertise, ensuring a lasting impact on future pediatric oncology research and clinical translation.
Potential Socio-Economic and Societal Impact
The project's impact extends beyond academia, with significant socio-economic and societal benefits:
- Accelerated drug development: By streamlining target validation and therapy optimization, VAGABOND contributes to reducing the time and cost of developing treatments for pediatric cancers.
- Improved patient outcomes: The identification of novel, personalized therapeutic approaches has the potential to increase survival rates and reduce long-term treatment side effects in children.
- Economic benefits: Strengthening collaboration between research institutions, biotech companies, and pharmaceutical partners fosters innovation-driven economic growth and reinforces Europe's position in pediatric oncology research.
- Training the next generation: The project has successfully prepared highly skilled researchers who will continue to drive innovation in translational medicine, precision oncology, and drug development.
VAGABOND has significantly advanced pediatric cancer research by:
Identifying and validating novel therapeutic targets across eight difficult-to-treat pediatric cancers.
Developing innovative preclinical models, including 3D tumor cultures and single-cell transcriptomics.
Pioneering novel immunotherapy strategies, such as dual-target CAR-T and TCR therapies, to enhance treatment efficacy and overcome tumor resistance.
Enhancing liquid biopsy approaches, enabling non-invasive monitoring of chemotherapy resistance and paving the way for personalized treatment strategies.
Expected Results Until the End of the Project
By the conclusion of VAGABOND, the project aims to:
✅ Refine and validate preclinical models to facilitate the transition of promising therapies into clinical testing.
✅ Strengthen interdisciplinary collaborations between academia, industry, and hospitals to accelerate drug development.
✅ Disseminate findings through high-impact publications, scientific conferences, and engagement with regulatory bodies.
✅ Equip ESRs with critical expertise, ensuring a lasting impact on future pediatric oncology research and clinical translation.
Potential Socio-Economic and Societal Impact
The project's impact extends beyond academia, with significant socio-economic and societal benefits:
- Accelerated drug development: By streamlining target validation and therapy optimization, VAGABOND contributes to reducing the time and cost of developing treatments for pediatric cancers.
- Improved patient outcomes: The identification of novel, personalized therapeutic approaches has the potential to increase survival rates and reduce long-term treatment side effects in children.
- Economic benefits: Strengthening collaboration between research institutions, biotech companies, and pharmaceutical partners fosters innovation-driven economic growth and reinforces Europe's position in pediatric oncology research.
- Training the next generation: The project has successfully prepared highly skilled researchers who will continue to drive innovation in translational medicine, precision oncology, and drug development.