LABORATORY OF NEURAL TUMORS

Principal Investigator (Name, MD/PhD)

Miguel F. Segura

Research Team

María José Pérez García, Postdoctoral Researcher & Project Manager

Khloud Abdo Elsharawy, Postdoctoral Researcher

Isabel de Rojas de Pablo, Postdoctoral Researcher

Adrià Molero Valenzuela, PhD Researcher

Marta Miera Maluenda, PhD Researcher

María Gallego Rodríguez, PhD Researcher

Gal·la Farreny Fernández, PhD Researcher

María Jesús Rodríguez Rodríguez, Laboratory Technician

Clinical Associated Researchers

Lucas Moreno, MD PhD. Head of the Childhood Cancer and Blood Disorders Group. Expertise in drug development and clinical trials.

Anna Llort, MD PhD. Pediatric Oncologist and institutional lead for pediatric brain tumors.

María Pérez-Torres, MD. Pediatric Oncologist.

Mariona Morell Daniel, MD. Pediatric Oncologist.

Marina Ortiz Palacios, MD. Pediatric Oncologist.

BACKGROUND

Pediatric cancer is a distinct disease entity with biological and clinical features that differ substantially from those of adult tumors, including etiology, tumor biology, treatment response, and prognosis. Over the past two decades, the implementation of multimodal treatment strategies—combining chemotherapy, radiotherapy, surgery, and targeted agents—has increased overall survival to around 80%. However, this progress has not benefited all patients equally. Children with certain tumor types continue to face poor outcomes, and many survivors experience severe long-term treatment-related toxicities. Developing more effective therapies for patients with high-risk disease, while reducing the short- and long-term side effects of current treatments, therefore remains an urgent clinical need.

Tumors of the nervous system are the most common solid malignant tumors in childhood and the leading cause of cancer-related death in children. Our laboratory is primarily focused on the development and implementation of epigenetic therapies, which target regulators of gene expression and, in turn, modulate multiple genes, pathways, and cellular processes without altering the DNA sequence itself. We study both neuroblastoma, a pediatric solid tumor of the peripheral nervous system, and pediatric brain tumors of the central nervous system, including ependymoma, medulloblastoma, and high-grade glioma, among others. Moreover, we are expanding our research toward more translational approaches, including projects linked to the initiation of clinical trials and the collection of liquid biopsy samples, in order to facilitate the transfer of our findings into clinical applications for pediatric cancer patients.

RESEARCH STRATEGY AND SCOPE

The research strategy of the Neural Tumors Lab is based on the following research lines:

Unveiling the epigenetic drivers of metastatic neuroblastoma

Approximately half of neuroblastoma patients present with metastatic disease at diagnosis, most frequently involving bone, bone marrow, lymph nodes, liver, and lungs, being metastatic relapse the leading cause of death of the disease. Increasing evidence indicates that epigenetic deregulation plays a critical role in neuroblastoma initiation, progression, and metastatic dissemination. We therefore hypothesize that systematic characterization of chromatin architecture alterations and therapeutic targeting of epigenetic vulnerabilities will advance our understanding of neuroblastoma metastasis and uncover novel therapeutic opportunities.

Uncovering epigenetic vulnerabilities of neuroblastoma

Epigenetics determines which genes are turned on or off without altering the DNA sequence, largely by controlling how DNA is packaged within the cell. A key player in this process is the BAF complex, a chromatin remodeler that neuroblastoma cells rely on to sustain proliferation and metastatic potential. Recent work in our laboratory has identified ARID1A/ARID1B as a promising vulnerability within the BAF complex, and this opened up two new research branches: (1) The development of small molecules to disrupt this dependency and inhibit tumor growth and (2) the use of PROTACs and specific inhibitors of SMARCA4 as a synthetic lethality strategy for ARID1A/B mutated patients.

Drug development: Moving forward to early-phase clinical trials

We are interested in testing the therapeutic potential of new synthetic or natural compounds which can represent clear advantages (i.e. increased effectiveness, reduced toxicities) compared to traditional chemotherapy. We have a clinically representative panel of pediatric solid tumor cell lines and preclinical mouse models to test the efficacy and safety of new drugs aimed to improve the efficacy and safety of currently available treatments. Currently, we are evaluating the therapeutic potential of ABTL0812 in pediatric tumors, both preclinically but also in a “first in child” Phase I clinical trial.

Translational precision oncology for pediatric neural tumors: Liquid biopsy

Liquid biopsy is a minimally invasive approach that enables the analysis of tumor-derived material in biofluids such as blood. In this project, we investigate circulating tumor DNA (ctDNA) as a biomarker for the molecular characterization and clinical monitoring of pediatric brain tumors and neuroblastoma. ctDNA analysis can provide clinically relevant information on tumor burden, tumor-associated genetic alterations, and disease dynamics over time. By allowing serial sampling, this strategy offers an attractive alternative to repeated invasive procedures. Our aim is to evaluate the potential of ctDNA to improve diagnosis, support treatment monitoring, and enable earlier detection of relapse. Ultimately, this work seeks to advance more precise, dynamic, and less invasive approaches for the management of pediatric malignancies.

Advancing in brain tumors research

Because pediatric brain tumors are the most common solid malignancies in children and still have limited treatment options resulting in poor overall survival, one of the laboratory’s main objectives is to develop new therapeutic strategies for these tumors. To this end, we are generating novel preclinical models of pediatric ependymoma to better recapitulate tumor biology and support translational research and evaluating the therapeutic potential of novel experimental compounds in vitro, including SWI/SNF inhibitors currently explored in our neuroblastoma research lines. Moreover, we aim to advance immunotherapy in pediatric brain tumors by identifying tumor-specific membrane proteins that can serve as targets for the development of more precise and effective therapeutic strategies.

ONGOING COMPETITIVE PROJECTS:

Ref. PI23/01144. Exploiting epigenetic vulnerabilities in metastatic neuroblastoma. Instituto de Salud Carlos III. PI: Miguel F. Segura.

Summary: Neuroblastoma is a cancer of the sympathetic nervous system, and is the most common solid tumor of childhood, representing ~15% of cancer deaths in children. While patients with localized disease have seen significant advances in their outcome, improvement in survival for patients with metastatic disease has been more limited. The liver, bone and bone marrow and lymph nodes are among the most common metastatic sites of neuroblastoma patients, which constitute a “reservoir” of tumor cells that persistently reside in patients following local and systemic cancer therapy. Their elimination continues to represent the most difficult challenges for neuroblastoma patients. Furthermore, the lack of clinically-representative models of neuroblastoma metastasis is hindering the development of therapies to target this subpopulation of cells. Our hypothesis is that metastatic cells can colonize distant organs thanks to the re-organization of their epigenetic landscape thanks to chromatin remodelers such as the SWI/SNF complex. We plan to validate our hypothesis through the following objectives: i) characterization of the epigenetic landscape of metastatic neuroblastoma; ii) characterize the transcriptomic map of SWI/SNF-regulated genes in neuroblastoma metastasis; iii) development of an epigenetic therapy based on the inhibition of chromatin remodeling complexes iv) development of more sensitive tools to diagnose and target neuroblastoma metastasis. To complete these tasks, we will use unique neuroblastoma metastasis mouse models combined with genomic analyses (ATACseq, RNAseq) and development of new compounds (SWI/SNF inhibitors) and diagnostic tools.

Ref. MONALISA_HE-MISS2023. MONALISA: A SIOPEN pragmatic clinical trial to MOnitor NeuroblastomA relapse with LIquid biopsy Sensitive Analysis. PI: Lucas Moreno.

Summary: High-risk neuroblastoma accounts for 15% of cancer related-deaths in children. Half of the >1500 patients yearly diagnosed with neuroblastoma in the EU have high-risk disease, which will relapse or progress in half these cases after first-line treatment. Relapsed neuroblastoma is aggressive and often therapy-resistant. Monitoring for disease relapse and therapy response is crucial for the survival chance of these patients. The current standard-of-care for monitoring are imaging technologies and bone marrow assessment, which are costly, invasive and a burden for children, who often require anesthesia. These drawbacks limit how often is monitored. More sensitive, less invasive and less toxic monitoring techniques are needed. The mutational spectrum often changes in recurring tumors, which may explain therapy resistance and provide additional druggable targets. Imaging, however, provides no information about molecular characteristics. Liquid biopsy tests are minimally invasive, allow frequent sampling and sensitively detect tumor molecular markers in tumor-derived DNA and messenger RNA circulating in peripheral blood. MONALISA aims to close existing gaps and establish liquid biopsies as standard-of-care to monitor relapsed/refractory neuroblastoma, as a blueprint for other pediatric cancers. Reliable, early assessment of molecular progression or relapse is the main aim of the pragmatic randomized clinical trial proposed in MONALISA. We develop a digital decision support tool to help oncologists use the new monitoring and apply patient-reported outcomes to integrate patient viewpoints and assess the effect of minimally invasive, liquid biopsy diagnostics on quality of life. We will establish whether events can be detected earlier using liquid biopsy monitoring, and whether better overall survival is enabled by earlier diagnosis and treatment interventions. This essential step towards personalized medicine will support reliable disease monitoring under treatment. “This action is part of the Cancer Mission cluster of projects on ‘‘Diagnostics and Treatment (diagnostics).

Ref. HRCI/JOINT_FUNDING_SCHEME/2022/SEGURA. Development of mRNA vaccines for children with high-risk neuroblastoma.

Summary: Neuroblastoma is one of the most aggressive childhood cancers contributing to 15% of cancer related childhood deaths. At diagnosis half of the patients have a metastatic tumour and recurrence is very common. Despite advances in available therapies, children with drug-resistant and relapsed neuroblastoma have a dismal outlook with 5-year survival rates of less than 20%, highlighting the need for new treatments. Immunotherapies, including anti-tumour vaccines, hold great promise to effectively target the tumour while generating fewer side effects and associated toxicities. This is achieved through the mechanism of action of vaccines that teach the immune system to identify and combat the tumour offering long term protection against recurrence. It is also forecasted that the success of COVID-19 messenger ribonucleic acid (mRNA) vaccines is set to boost the therapeutic oligonucleotide market to reach $4.5B by 2027 globally. This project aims to develop the first mRNA vaccine against high-risk neuroblastoma. Specifically, we will select two well characterised neuroblastoma cell surface antigens to be targeted in a mRNA vaccine. This vaccine will be delivered using RALA peptide, based on previous studies of the applicant team. The RALA/mRNA nanoparticles will be characterized for shape, surface charge, stability and immunogenicity. The transfection efficiency of the vaccine will be determined in vitro using DC 2.4 cells (murine dendritic cell line) and in THP-1 cells (human monocytic cell line). For the immunogenicity studies, C57 BL/6 mice will receive the vaccine and blood samples will be collected to analyse specific antibodies and cytokine secretion. The therapeutic and prophylactic potential of RALA/mRNA vaccine will be analysed using a metastatic model of neuroblastoma and a PDX humanized mouse model. Finally, we will evaluate the regulatory options to ensure an efficient therapy translation to the clinical setting. This will include market analysis as well as intellectual property and orphan drug designation applications.

Ref. 2024 PROD 00054. Targeting chromatin remodelers for cancer therapy.

Summary: Neuroblastoma (NB), a pediatric tumor, poses significant challenges due to its high mortality rates and resistance to conventional treatments. Many high-risk patients do not achieve a cure, and even survivors may suffer severe long-term side effects. Current therapies often fall short in cases of relapse or disease progression.

NB's ability to metastasize and treatment resistance involves genomic reprogramming facilitated by aberrant function of epigenetic regulators such as the mSWI/SNF chromatin remodeling complex. Lately, our group have made crucial discoveries, linking elevated expression of specific subunits (e.g., SMARCA4) with poor prognosis. Functionally, we found that by silencing only two subunits (ARID1A/B) the complex was destabilized, which inhibited tumor growth and metastasis. Inhibition of protein-protein interactions in the SWI/SNF complex innovates in the development of a first-in-class family of drugs. These compounds demonstrated anti-proliferative properties across a wide range of NB cell lines, with high selectivity and minimal impact on cells lacking ARID1A/B subunits. The main objective of this project is to lead optimization of our novel compounds, study their efficacy in clinically-representative NB models and establish an IP and a commercial strategy for the transition of this family of compounds to the market.

Compared to the standard NB treatment, our strategy offers a distinct mechanism of action by reversing epigenetic alterations without causing DNA damage in healthy tissues. This approach promises enhanced treatment efficacy and reduced long-term side effects. Moreover, our solution may improve the quality of life in pediatric cancer patients, reducing the physical and emotional burden on affected families as well as improving the outcomes for high-risk NB cases. This novel epigenetic treatment will also contribute to the growth of the epigenetics market, which is projected to exhibit substantial growth in the coming years.

Ref: NeuVac – a multiepitope mRNA vaccine for high-risk neuroblastoma

Summary: Neuroblastoma is one of the most aggressive childhood cancers contributing to 15% of cancer related childhood deaths. At diagnosis half of the patients have a metastatic tumour and recurrence is very common. Despite advances in available therapies, children with drug-resistant and relapsed neuroblastoma have a dismal outlook with 5-year survival rates of less than 20%, highlighting the need for new treatments. Immunotherapies, including anti-tumour vaccines, hold great promise to effectively target the tumour while generating fewer side effects and associated toxicities. This is achieved through the mechanism of action of vaccines that teach the immune system to identify and combat the tumour offering long-term protection against recurrence. This project aims to design and manufacture a multiepitope mRNA vaccine against high-risk neuroblastoma. Specifically, we will characterise and shortlist neuroblastoma cell surface antigens to be targeted in a mRNA vaccine. This vaccine will be delivered using RALA peptide, based on previous studies of the applicant team. We will characterise the RALA/mRNA formulation, stability and assessment of immune response. We will identify an appropriate tumour model in vivo and determine the therapeutic response to the vaccine in a metastatic model of neuroblastoma in a clinically relevant scenario. Should these critical research activities provide positive results, we are then ideally placed to move to the next stage of the development process (toxicology) and this provides the data package to enable further application to the orphan drug designation application and first children clinical trials.

Ref. BARRERA/BECA/SEGURA/2024. Unlocking the Power of Liquid Biopsy: Advancing Precision Medicine in Pediatric Brain Tumors.

Summary: Los tumores del sistema nervioso central son el tumor sólido pediátrico más frecuente representando hasta el 20-25% de todos los casos. A pesar de los múltiples avances en oncohematología pediátrica, muchos de estos tumores siguen teniendo un pronóstico desfavorable. Las herramientas actuales para su diagnóstico y monitorización presentan limitaciones, tanto las pruebas de imagen, que pueden llevar a interpretaciones confusas especialmente después de la cirugía; como la biopsia del tejido, que no es representativa de la heterogeneidad tumoral y puede interferir en el neurodesarrollo, causando daños a largo plazo. Por estas razones es necesario innovar y desarrollar nuevos métodos de detección que permitan un abordaje clínico menos invasivo de estos tumores. La hipótesis de este proyecto es que el análisis del ADN tumoral circulante (ctDNA) obtenido en muestras de sangre o líquido cefalorraquídeo de los pacientes con tumores cerebrales pediátricos (TCP) puede proporcionar información clínicamente relevante, posicionándose como una herramienta útil y mínimamente invasiva para el diagnóstico, monitorización y seguimiento de estos casos. Esta hipótesis se validará mediante los siguientes objetivos:

i. Obtención de muestras y recogida de casos retrospectivos. ii. Identificación de biomarcadores representativos en los distintos tipos de TCPs. iii. Prueba piloto para la validación y optimización de la técnica de detección.

Estas tareas se completarán mediante la recolección de muestras biológicas y el uso de tecnologías avanzadas como PCR digital y secuenciación de nueva generación (NGS) para detectar alteraciones moleculares recurrentes del ctDNA de las muestras. Este proyecto tiene el potencial de transformar el diagnóstico y seguimiento de los tumores cerebrales pediátricos, mejorando la supervivencia y calidad de vida de los niños afectados, al tiempo que ofrece esperanza y bienestar a sus familias.

Ref. 2025 LLAV 00002. AURA-BRAIN: AI-powered Utility for Real-time Assessment and decision-making in pediatric Brain tumors using liquid biopsy.

Summary: represent the most common solid group of cancers in children, accounting for approximately 25% of all pediatric tumors. Despite advances in therapeutic strategies, PBTs remain a leading cause of cancer-related mortality in children. A majority of patients experience sudden tumor progression, therapy resistance, and/or relapse, underscoring the urgent need for more effective follow-up and intervention protocols.

Current monitoring approaches, such as imaging, are unable to provide molecular insights into tumor evolution, frequently exhibiting altered mutational landscapes, which are critical for addressing therapy resistance and identifying new druggable targets. In this sense, liquid biopsy has emerged as a promising minimally invasive technique, capable of detecting circulating-tumor DNA (ctDNA) in peripheral blood and cerebrospinal fluid (CSF). This approach offers the potential for frequent sampling, sensitive detection of tumor biomarkers, and real-time insights into tumor dynamics. In this proposal, we submit a project that aims to translate current PBT research knowledge into clinical practice by developing liquid biopsy technologies that will enable better clinical management of patients at diagnosis, treatment and monitoring stages. The primary objective is to develop and validate a next generation sequencing (NGS)-based protocol using circulating tumor nucleic acids as biomarkers. This technology will be supported by an artificial intelligence (AI) decision support system that integrates both genomic and clinical parameters to evaluate clinical outcomes. Its goal is to provide more accurate and less invasive methods for molecular diagnosis, tumor burden monitoring, treatment response assessment, disease progression tracking, and early relapse detection, ultimately improving survival outcomes for children with brain tumors.

Ref: HORIZON-MISS-2025-02-CANCER-04-101289276. Phase I/II trial of an Oral ER-stress iNducer in relapsed/refractory neuroblastoma and paediatric solid tumours.

Summary: Childhood cancer is the leading cause of disease-related death in children, with high-risk neuroblastoma and other aggressive paediatric solid tumours representing a critical unmet need. Despite multimodal therapy, over half of children with relapsed or refractory disease do not achieve long-term survival, and those who do often suffer severe, lifelong toxicities. There is an urgent need for safer and more effective therapies.

Ibrilatazar (ABTL0812) is a first-in-class, orally administered anticancer agent that induces tumour cell death through endoplasmic reticulum stress and cytotoxic autophagy. Unlike conventional genotoxic chemotherapies, it spares DNA, offering a potentially safer profile highly relevant in children. In adult patients with advanced solid tumours, ibrilatazar has shown an excellent safety record and early efficacy in Phase I/II trials, with long-term stabilisation in heavily pre-treated patients, thereby supporting its evaluation in the paediatric population.

Preclinical studies in neuroblastoma models, including MYCN-amplified and chemoresistant cell lines, demonstrate that ibrilatazar reduces tumour growth, downregulates MYCN expression, and enhances standard chemotherapies and differentiating agents.

Building on this evidence, PHOENIX will conduct a first-in-child, multicentre Phase I/II clinical trial of ibrilatazar in relapsed/refractory neuroblastoma and other aggressive solid tumours. The trial will test combinations with irinotecan-temozolomide and selected immunotherapies (anti-GD2, anti-VEGF), aligned with our preclinical findings. In parallel, a comprehensive translational programme will integrate pharmacokinetic, pharmacodynamic, genomic, and immunological biomarker studies, aiming to enable patient stratification, early treatment monitoring, and improved trial inclusiveness by addressing social determinants of health. Thus, PHOENIX seeks to deliver a safer, more effective therapeutic alternative for children with high-risk cancers.

SELECTED PUBLICATIONS

1. Miera-Maluenda M, Pérez-Torres M, Mañas A, Rubio-San-Simón A, Butjosa-Espín M, Ruiz-Duran P, Seoane JA, Moreno L, Segura MF. Advances in the approaches used to repurpose drugs for neuroblastoma. Expert Opin Drug Discov. 2024 Nov;19(11):1309-1319. doi: 10.1080/17460441.2024.2402413. Epub 2024 Sep 11. PMID: 39258785.

2. Murphy C, Devis-Jauregui L, Struck R, Boloix A, Gallagher C, Gavin C, Cottone F, Fernandez AS, Madden S, Roma J, Segura MF*, Piskareva O*. In vivo cisplatin-resistant neuroblastoma metastatic model reveals tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as an independent prognostic factor of survival in neuroblastoma. PLoS One. 2024 May 29;19(5):e0303643. doi: 10.1371/journal.pone.0303643. PMID: 38809883; PMCID: PMC11135766. (* corresponding authors).

3. Pérez-García MJ, Segura MF. Maintaining excellent outcomes: the impact of age cutoff reclassification on reduced therapy for neuroblastoma patients. Transl Pediatr. 2023 Nov 28;12(11):1926-1930. doi: 10.21037/tp-23-391. Epub 2023 Nov 23. Erratum in: Transl Pediatr. 2024 Aug 31;13(8):1514. doi: 10.21037/tp-2024-02. PMID: 38130585; PMCID: PMC10730960.

4. Jiménez C, Moreno L, Segura MF. Epigenetic therapies for neuroblastoma: immunogenicity awakens. Mol Oncol. 2023 May;17(5):718-721. doi: 10.1002/1878-0261.13404. Epub 2023 Mar 8. PMID: 36840349; PMCID: PMC10158771.

5.- Jiménez C, Antonelli R, Nadal-Ribelles M, Devis-Jauregui L, Latorre P, Solé C, Masanas M, Molero-Valenzuela A, Soriano A, Sánchez de Toledo J, Llobet-Navas D, Roma J, Posas F, de Nadal E, Gallego S, Moreno L, Segura MF. Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program. Mol Cancer. 2022 Sep 3;21(1):175. doi: 10.1186/s12943-022-01643-4. PMID: 36057593; PMCID: PMC9440539.

6.- Segura MF, Soriano A, Roma J, Piskareva O, Jiménez C, Boloix A, Fletcher JI, Haber M, Gray JC, Cerdá-Alberich L, Martínez de Las Heras B, Cañete A, Gallego S, Moreno L. Methodological advances in the discovery of novel neuroblastoma therapeutics. Expert Opin Drug Discov. 2022 Feb;17(2):167-179. doi: 10.1080/17460441.2022.2002297. Epub 2021 Nov 22. PMID: 34807782.

7.- Boloix A, Feiner-Gracia N, Köber M, Repetto J, Pascarella R, Soriano A, Masanas M, Segovia N, Vargas-Nadal G, Merlo-Mas J, Danino D, Abutbul-Ionita I, Foradada L, Roma J, Córdoba A, Sala S, de Toledo JS, Gallego S, Veciana J, Albertazzi L, Segura MF*, Ventosa N*. Engineering pH-Sensitive Stable Nanovesicles for Delivery of MicroRNA Therapeutics. Small. 2022 Jan;18(3):e2101959. doi: 10.1002/smll.202101959. Epub 2021 Nov 16. PMID: 34786859. (*corresponding authors).

8.- Masanas M, Masiá N, Suárez-Cabrera L, Olivan M, Soriano A, Majem B, Devis-Jauregui L, Burgos-Panadero R, Jiménez C, Rodriguez-Sodupe P, Boloix A, Toledano I, Guillén G, Navarro A, Llobet-Navas D, Villanueva A, Sánchez de Toledo J, Roma J, Noguera R, Moreno L, Krauss R, Gallego S, Santamaria A*, Segura MF*. The oral KIF11 inhibitor 4SC-205 exhibits antitumor activity and potentiates standard and targeted therapies in primary and metastatic neuroblastoma models. Clin Transl Med. 2021 Oct;11(10):e533. doi: 10.1002/ctm2.533. PMID: 34709738; PMCID: PMC8516339. (*corresponding authors).

9.- París-Coderch L, Soriano A, Jiménez C, Erazo T, Muñoz-Guardiola P, Masanas M, Antonelli R, Boloix A, Alfón J, Pérez-Montoyo H, Yeste-Velasco M, Domènech C, Roma J, Sánchez de Toledo J, Moreno L, Lizcano JM, Gallego S, Segura MF. The antitumour drug ABTL0812 impairs neuroblastoma growth through endoplasmic reticulum stress-mediated autophagy and apoptosis. Cell Death Dis. 2020 Sep 17;11(9):773. doi: 10.1038/s41419-020-02986-w. PMID: 32943619; PMCID: PMC7498451.

10.- Antonelli R, Jiménez C, Riley M, Servidei T, Riccardi R, Soriano A, Roma J, Martínez-Saez E, Martini M, Ruggiero A, Moreno L, Sánchez de Toledo J, Gallego S, Bové J, Hooker JM, Segura MF. CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models. Cancers (Basel). 2020 Jul 16;12(7):1922. doi: 10.3390/cancers12071922. PMID: 32708733; PMCID: PMC7409080.

11.- Qadeer ZA, Valle-Garcia D, Hasson D, Sun Z, Cook A, Nguyen C, Soriano A, Ma A, Griffiths LM, Zeineldin M, Filipescu D, Jubierre L, Chowdhury A, Deevy O, Chen X, Finkelstein DB, Bahrami A, Stewart E, Federico S, Gallego S, Dekio F, Fowkes M, Meni D, Maris JM, Weiss WA, Roberts SS, Cheung NV, Jin J, Segura MF, Dyer MA, Bernstein E. ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures. Cancer Cell. 2019 Nov 11;36(5):512-527.e9. doi: 10.1016/j.ccell.2019.09.002. Epub 2019 Oct 17. PMID: 31631027; PMCID: PMC6851493.

12.- Soriano A, Masanas M, Boloix A, Masiá N, París-Coderch L, Piskareva O, Jiménez C, Henrich KO, Roma J, Westermann F, Stallings RL, Sábado C, de Toledo JS, Santamaria A, Gallego S, Segura MF. Functional high-throughput screening reveals miR-323a-5p and miR-342-5p as new tumor-suppressive microRNA for neuroblastoma. Cell Mol Life Sci. 2019 Jun;76(11):2231-2243. doi: 10.1007/s00018-019-03041-4. Epub 2019 Feb 15. PMID: 30770954; PMCID: PMC6502783.

13.- Jubierre L, Soriano A, Planells-Ferrer L, París-Coderch L, Tenbaum SP, Romero OA, Moubarak RS, Almazán-Moga A, Molist C, Roma J, Navarro S, Noguera R, Sánchez-Céspedes M, Comella JX, Palmer HG, Sánchez de Toledo J, Gallego S, Segura MF. BRG1/SMARCA4 is essential for neuroblastoma cell viability through modulation of cell death and survival pathways. Oncogene. 2016 Sep 29;35(39):5179-90. doi: 10.1038/onc.2016.50. Epub 2016 Mar 21. PMID: 26996667.

ACTIVE COLLABORATIONS WITH INDUSTRY: (Name, country)

Ability Pharma S.L. (Barcelona, Spain)

OMICA Biomed S.L.

PAST MEMBERS: (Name, actual position)

-Dr. Luz Jubierre Zapater (2013-2017). Senior Research Scientist at MSKCC, NY, USA.

-Dr. Laia París-Coderch (2014-2017). Currently working as Validation and GMP Junior Consultant at TDV SL.

-Dr. Aroa Soriano (2012-2020). Currently leading the Personalized Medicine Program at Vall Hebron Hospital.

-Dr. Marc Masanas (2015-2022). High-school Teacher.

-Dr. Roberta Antonelli (2016-2022). Research and Development Senior Scientist and Scientific Project Manager at the Institute of Microelectronics of Barcelona (IMB-CNM, CSIC), Barcelona.

-Dr. Carlos Jiménez Jiménez (2015-2022), Postdoctoral Researcher at the Human Technopole Center (Milan).

Principal Investigator:

Aroa Soriano, PhD & Lucas Moreno, MD, PhD

Research Team:

- Raquel Hladun, MD: PhD researcher and Pediatric Oncologist

- Gabriela Guillén, MD: PhD researcher and Pediatric Surgeon

- Ainara Magdaleno: Laboratory Technician

- Lorena Valero, MD: Pediatric Oncologist

- Andrea Vilaplana: Biologist

- Alba Fernández, MD: Pediatric Oncologist

Collaborators or Associated Researchers or Clinical Associated Researchers:

- Luís Gros, MD: Pediatric Oncologist

- Anna Llort, MD, PhD: Pediatric Oncologist

- Constantino Sábado, MD, PhD: Pediatric Oncologist

- Maria Paula Pérez, MD: Pediatric Oncologist

- Marta Sesé, PhD: Biologist

- Javier Hernández, PhD: Biologist

- Elena Martínez, MD, PhD: Pathologist

- Marta Garrido, MD: Pathologist

- Alexandra Navarro, MD: Pathologist

- Jessica Camacho, MD, PhD: Pathologist

- Josep Roma, PhD: Sarcoma Lab PI

- Miguel Segura, PhD: Neural Tumors PI

- José Andrés Molino, MD: Pediatric Surgeon

- Sergio López, MD: Pediatric Surgeon

- Mª Antonia Poca: Pediatric Neurosurgeon

- Katiuska Rosas: Pediatric Neurosurgeon

- Diego Fernando Lopez: Pediatric Neurosurgeon

- Josefa Elida Vázquez: Radiologists

- Luis Riera: Radiologists

- Ana Coma: Radiologists

- Joan Albert Prat: Radiologists

- Angel Sánchez-Montañez: Radiologists

- José Miguel Escudero: Radiologists

- Lucia Riaza: Radiologists

- Ignacio Delgado: Radiologists

BACKGROUND

Revolution of Personalized Medicine in cancer care: The recent advances of anticancer precision medicine drugs have changed the paradigm of cancer treatment, particularly in tumors with single driving genetic alteration or oncogene addiction. Some of the most prominent examples of targeted drugs in pediatric cancers include NTRK, BRAF or ALK inhibitors. These novel drugs have completely changed frontline treatment practice for small subgroups of patients across tumor types, which need to be identified upfront.

Deep molecular profiling helps to improve diagnosis, and molecular diagnostics is already included in many childhood cancer entities in the WHO classification. Moreover, it refines prognostic stratification by identifying poor/good prognosis subgroups which need different treatments. In addition, it allows the identification of cancer predisposition syndromes which have major implications in management and surveillance, not only for the patients but also for their families.

The main goal of our Personalized Medicine Program is to build, implement and consolidate a strong personalized medicine program based on molecular profiling approaches to improve diagnosis accuracy, prognosis, treatment and identification of cancer predisposition syndromes for all children and adolescents with cancer in Spain. Our final aim is to offer every child with cancer the best possible chance of survival.

The personalised medicine program consists of a true multidisciplinary team formed by pediatric oncologists, surgeons, pathologists, radiologists, geneticists, molecular translational researchers and bioinformaticians who are committed to their work.

Our group also works in several Data Science projects, particularly focused in neuroblastoma. The genomic data generated in sequencing programs (COMIK, MAPPYACTS among others) together with clinical data generated within clinical trials (such as BEACON) and through the INRG collaboration (www.inrgdb.org) is further analysed and combined to identify novel biomarkers and targets that can be implemented in the clinic; also in collaboration with international data sharing initiatives.

RESEARCH STRATEGY AND SCOPE

The Pediatric Oncology Personalized Medicine Program is composed of:

COMIK (Cancer OMIcs for Kids) Program

• COMIK is the personalised medicine program of Vall d’Hebron Hospital for children, adolescents and young adults with relapsed/refractory solid tumours. COMIK includes patients from all the autonomous communities. Within COMIK programme we perform whole exome sequencing (WES) and RNA sequencing to obtain the complete profile of molecular alterations of the patients’ tumors to improve the access of children and adolescents with cancer to innovative therapies and targeted therapies within basket clinical trials. Our pre-screening platform is the only one in Spain based on WES and RNAseq molecular profiling.

• Functional Screening: Clinical pediatric precision oncology platforms have already identified actionable molecular targets in approximately 60% of pediatric cancers by applying next generation sequencing technologies. Despite the immense knowledge generated through sequencing efforts the remaining 40% of the children and adolescents lack actionable alterations indicating significant currently unmet needs in precision medicine programs. New targets and combinations must be identified combining profiling with functional data. We want to integrate the results of deep molecular profiling with novel functional screening tools, to increase and improve the therapeutic options available for pediatric patients.

• PDOX (Patient-derived orthotopic xenografts): COMIK program includes the generation of PDOX. Currently, we have established 50 orthotopic PDX models of pediatric solid tumors in collaboration with Dr. Alberto Villanueva from ICO/IDIBELL. Primary tumors and metastases from different locations were surgically grafted in their original locations in immunocompromised mice, maintaining their three-dimensional tissue structure. PDOX are unique valuable tools for

pediatric drug development, the discovery of molecular mechanisms for drug efficacies and combinations and in personalized medicine programs.

SEHOP-PENCIL (Personalised Medicine for Cancer in Children in Spain) Program

While France, the UK or Germany have now implemented routine next generation sequencing (NGS) panels and WES and RNAseq for all childhood cancer patients at diagnosis and relapse, sequencing has not yet been widely incorporated by the Spanish health care system for pediatric cancer patients. SEHOP-PENCIL is the Precision Medicine Strategy of our national scientific society (SEHOP-Sociedad Española de Hematología y Oncología Pediátrica) to create a network of eight hubs, all of which will be accessible to all hospitals treating pediatric cancer patients across our territory.

We want to implement molecular profiling approaches to improve diagnosis accuracy, treatment and identification of cancer predisposition syndromes for all children and adolescents with cancer in Spain. Moreover, we want to evaluate the efficacy and cost-effectiveness of these personalized medicine approaches and facilitate the regulatory and administrative pathway for their introduction in clinical care in the Spanish national healthcare system, ensuring equity and excellence in care for Spanish children and adolescents with cancer.

MAPPYACTS (MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification)

We have also collaborated in a European study of personalised medicine in paediatric cancer called MAPPYACTS. MAPPYACTS is a world-leading personalised medicine program that has changed the model of care for children with cancer in France. Vall d’Hebron was the only hub outside France accredited for genomic analyses of Spanish patients within this trial. Our participation in MAPPYACTS2 will start during 2022.

ONGOING COMPETITIVE PROJECTS:

• PI21/01661 (AES-ISCIII)- PI: Lucas Moreno & Aroa Soriano. COMIK 2.0: Integration of a genomic and functional screening platform for pediatric precision oncology. From 2022 to 2024. Amount granted: 214.170 €.

Our group started the personalized medicine program COMIK in 2016-2017, which has conducted WES in more than 100 pediatric patients to date. The program included patients with high-risk, refractory and relapsed solid tumours in the Paediatric Haematology & Oncology Unit of the Vall d'Hebron Hospital. COMIK2.0 is to enlarge the COMIK project including functional testing in addition to WES & RNASeq and facilitating referrals from all centres in Spain.

Nowadays, molecular screening is mandatory for 14 early phase trials in Spain and 4 of them require deep genomic screening with WES/WGS/RNAseq (i.e AcSe-ESMART [EudraCT 2016-000133-40]) Our main goal in this project is the development of a pre-screening platform for pediatric basket trials for relapsed & refractory childhood and adolescent cancers to maximize chances of antitumor efficacy and increase access of the pediatric patients to innovative therapies.

We also propose to integrate molecular analyses with a functional screening assay to improve the ability to predict clinical benefit of therapeutic options for pediatric patients. Functional screening assays perfectly complement molecular analysis in personalized medicine platforms when actionable alterations are not found or when we identify multiple genetic alterations. Our goal is to develop more accurate predictive pre-screening methods to offer the best therapeutic option for pediatric patients with relapsed and refractory tumors.

• PMP21/00073 (AES-ISCIII)-PI: Lucas Moreno. SEHOP-PENCIL Study: Personalised Medicine for Cancer in Children in Spain. From 2022 to 2025. Total amount: 1.890.703 €. VHIR coordinating group: 1.025.179,10

Incorporating high level personalized medicine programs in standard treatment of childhood cancer offers a unique opportunity to improve survival and reduce morbidities for all children.

The PENCIL project by the Spanish Society of Paediatric Haematology and Oncology has four major objectives: 1) To implement a nation-wide sequencing program offering access to next generation sequencing (NGS) panels at the time of diagnosis for high-risk cancers, whole exome/whole-genome sequencing (WES/WGS) and RNASeq at relapse, germline NGS panel or WGS to identify cancer predisposition syndromes and DNA methylation profiling for CNS tumours and sarcomas. 2) To develop tools to facilitate access to PerMed to all patients across Spain, by creating a network of clinicians and genomic hubs and molecular tumour boards. 3) To evaluate the implementation of PerMed into routine care for childhood cancer including cost-effectiveness and clinical outcomes. 4) To develop novel technologies that will overcome current limitations of diagnostic and surveillance approaches, such as liquid biopsy. The incorporation of PerMed into routine care will lead to improved diagnostic and prognostic information at diagnosis, increased access to novel targeted therapies at relapse and early identification and intervention on cancer predisposition syndromes for patients in all autonomous regions of Spain, resulting in major benefits for our society.

BEACON-BIO (Fights Kids Cancer)-IP: Lucas Moreno. Total amount:104.500 € VHIR coordinating group: 499.776 €

The BEACON trial (EudraCT 2012-000072-42) is a collaborative trial between the European consortia for early clinical trials and neuroblastoma research (ITCC and SIOPEN respectively)

for RRNB that started in 2013 that is now completed (n=225). In the first 160 patients, it evaluated three regimens (temozolomide, irinotecan-temozolomide and topotecantemozolomide) and bevacizumab (an anti-VEGF monoclonal antibody) showing improvements in response rates and survival, meeting trial pre-defined success criteria for progression-free survival (PFS). The Bevacizumab-Irinotecan-Temozolomide (BIT) combination may be more effective than irinotecan or bevacizumab separately: 2-year PFS was 49% for this arm. The trial was then amended to evaluate the addition of dinutuximab beta to topotecan-temozolomide chemotherapy following results from US trials with chemo-immunotherapy. 65 patients have been recruited and results will be available during Q4 2021 (Gray, Moreno & Wheatley). Currently, relapsed and refractory patients show different clinical phenotype and outcomes, but they are commonly grouped together in clinical trials. A crucial objective of this project will be to fully characterise these two populations.

SELECTED PUBLICATIONS (Top 10):

1. Berlanga P, Pierron G, Lacroix L, Chicard M, Adam de Beaumais T, Marchais A, Harttrampf AC, Iddir Y, Larive A, Soriano A, Hezam I, Chevassus C, Bernard V, Cotteret S, Scoazec JY, Gauthier A, Abbou S, Corradini N, André N, Aerts I, Thebaud E, Casanova M, Owens C, Hladun R, Michiels S, Delattre O, Vassal G, Schleiermacher G, Geoerger B. The European MAPPYACTS trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies. Cancer Discovery 2022.

2. Gargallo P, Bautista F, Juan-Ribelles A, Izquierdo E, Soriano A, de Rojas T, Escudero A, Lavarino C, Solano P, Hladun R, Rubio-San-Simón A, Martínez-Romera I, Calabria I, Olaciregui NG, Castañeda-Heredia A, de Álava E, Pérez-Martínez A, Astigarraga I, Patiño-García A, Alonso J, Fernández-Teijeiro A, Cañete A & Moreno L. Current status of precision medicine in pediatric oncology in Spain: a consensus report by the Spanish Society of Paediatric Haematology and Oncology (SEHOP). Clinical and Translational Oncology. 2022 Feb. PMID: 35152364. DOI: 10.1007/s12094-021-02759-7.

3. Segura MF, Soriano A, Roma J, Piskareva O, Jiménez C, Boloix A, Fletcher JI, Haber M, Gray JC, Cerdá-Alberich L, Martínez de Las Heras B, Cañete A, Gallego S, Moreno L. Methodological advances in the discovery of novel neuroblastoma therapeutics. Expert Opin Drug Discov. 2022 Feb;17(2):167-179. doi: 10.1080/17460441.2022.2002297. Epub 2021 Nov 22. PMID: 34807782.

4. Masanas M, Masiá N, Suárez-Cabrera L, Olivan M, Soriano A, Majem B, Devis-Jauregui L, Burgos-Panadero R, Jiménez C, Rodriguez-Sodupe P, Boloix A, Toledano I, Guillén G, Navarro A, Llobet-Navas D, Villanueva A, Sánchez de Toledo J, Roma J, Noguera R, Moreno L, Krauss R, Gallego S, Santamaria A*, Segura MF*. The oral KIF11 inhibitor 4SC-205 exhibits antitumor activity and potentiates standard and targeted therapies in primary and metastatic

neuroblastoma models. Clin Transl Med. 2021 Oct;11(10):e533. doi: 10.1002/ctm2.533. PMID: 34709738; PMCID: PMC8516339. (*corresponding authors).

5. Alcon C, Manzano-Muñoz A, Prada E, Mora J, Soriano A, Guillén G, Gallego S, Roma J, Samitier J, Villanueva A, Montero J. Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance. Cell Death Dis. 2020 Aug 15;11(8):634. PMID: 32801295. DOI: 10.1038/s41419-020-02887-y.

6. Carrillo-Reixach J, Torrens L, Simon-Coma M, Royo L, Domingo-Sàbat M, Abril-Fornaguera J, Akers N, Sala M, Ragull S, Arnal M, Villalmanzo M, Cairo S, Villanueva A, Kappler R, Garrido M, Guerra L, Sábado C, Guillén G, Mallo M, Piñeyro D, Vázquez-Vitali M, Kuchuk O, Mateos ME, Ramírez G, López Santamaría M, Mozo Y, Soriano A, Grotzer M, Branchereau S, García de Andoin N, López-Ibor B, López-Almaraz R, Salinas JA, Torres B, Hernández F, Uriz JJ, Fabre M, Blanco J, Paris C, Bajciová V, Laureys G, Masnou H, Clos A, Belendez C, Guettier C, Sumoy L, Planas R, Jordà M, Nonell L, Czauderna P, Morland B, Sia D, Losic B, Annick Buendia M, Sarrias MR, Llovet JM, Armengol C. Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. J Hepatol. 2020 Aug;73(2):328-341. doi: 10.1016/j.jhep.2020.03.025. Epub 2020 Mar 30. PMID: 32240714.

7. Zarzosa P, Navarro N, Giralt I, Molist C, Almazán-Moga A, Vidal I, Soriano A, Segura MF, Hladun R, Villanueva A, Gallego S, Roma J. Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments. Clin Transl Oncol. 2017 Jan;19(1):44-50. doi: 10.1007/s12094-016-1557-2. Epub 2016 Oct 7. PMID: 27718156

PAST MEMBERS:

The success of our clinical trials unit has been possible thanks to the pioneering work by Soledad Gallego, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR.

Josep Sanchez de Toledo, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR.

Principal Investigator:

Lucas Moreno, MD, PhD & Raquel Hladun, MD

Research Team:

- Carlota Aguilera, Senior Study Coordinator

- Elena Andretta, Senior Study Coordinator

- Raquel Andreu, Data Manager

- Raquel Anta, Data Manager

- Marina Bonfill, Psycho-Oncologist

- Cristina Diaz de Heredia, Pediatric Oncologist

- Verónica Fernández, Study Nurse

- Paula Pérez Albert, Pediatric Oncologist

- Laura Romero, Study Nurse

- Lorena Valero, Pediatric Oncologist

- Pablo Velasco, Pediatric Oncologist

Clinical Associated Researchers:

- Luis Gros, MD: Pediatric Oncologist

- Anna Llort, MD, PhD: Pediatric Oncologist

- Constantino Sábado, MD: Pediatric Oncologist

- Luz Uría, MD: Pediatric Oncologist

- Maribel Benitez, MD: Pediatric Oncologist

- Laura Alonso, MD: Pediatric Oncologist

- Thais Murciano, MD: Pediatric Oncologist

- Laura Murillo, MD: Pediatric Oncologist

- Blanca Espinosa, MD: Pediatric Oncologist

- Anna Collado, MD: Pediatric Oncologist

- María Perez-Torres, MD: Pediatric Oncologist

- Ángela Menárguez, MD: Pediatric Oncologist

- Melissa Panesso, MD: Pediatric Oncologist

Collaborators:

- Marina Ortiz, MD: Pediatric Oncologist

- Josefa Elida Vázquez & Pediatric Radiology team

- Santiago Aguadé, Cristina Gámez & Nuclear Medicine team

- Nieves Martin & Pediatric Ophtalmology team

- Ferran Roses & Pediatric Cardiology team

BACKGROUND

Childhood cancer is the first cause of death due to disease in children. New drugs are needed to increase cure rates and reduce long-term sequelae of survivors. More than half of children with high-risk tumors, such as metastatic neuroblastoma, sarcomas or leukemias, or those with refractory or relapsed disease will not achieve a long-term cure.

Similarly, great advances have occurred in the development of novel drugs for non-malignant hematological conditions, leading to improved quality of life and avoidance of toxic therapies; our team focuses in the fields of hemolytic anemias such as sickle cell disease and pyruvate Kinase deficiency and bone marrow failure syndromes such as Fanconi anemia.

We have a wide clinical trial portfolio through our participation in the international ITCC consortium, with more than 50 clinical trials open at each given timepoint. Of those, more than 30 are early phase (phase 1 and phase 2), and many are first-in-child.

Our team receives patient consultations for participation in clinical trials from all regions of Spain and second opinion consultations are available through contact with the clinical team. If interested in participating in one of our clinical trials, please ask your primary physician to contact our team.

Over the past five years, we have developed and participated in multiple breakthrough academic and industry-driven clinical trials, such as the first-in-child, first-in-human trial of gene therapy for Fanconi anemia (reference Nat Med . 2019 Sep;25(9):1396-1401), the first-in-child trial of the ALK inhibitor ceritinib (Fischer/Moreno ref) and trials with oncolytic virus (EudraCT TVEC and AloCelyvir), CAR-T cells (BIANCA EudraCT 2017-005019-15) and cell therapies (ALVR-105 EudraCT 2021-003450-22) and larotrectinib for NTRK-positive tumours [SCOUT] (Neuro Oncol. 2022 Jun 1;24(6):997-1007).

The team has also participated and led practice-changing randomized trials, together with academic international consortia; such as the SCT Forum trial (Use of total body irradiation for SCT in childhood ALL), the EpSSG RMS 2005 trial (use of vinorelbine-cyclophosphamide as maintenance therapy in childhood rhabdomyosarcoma). The BEACON-Neuroblastoma trial, led by Dr. Lucas Moreno, evaluated the addition of bevacizumab and dinutuximab beta to chemotherapy in relapsed and refractory neuroblastoma. European sequencing project MAPPYACTS facilitate matching targeted therapies (Cancer Discov. 2022 May 2;12(5):1266-1281.).

RESEARCH STRATEGY AND SCOPE

Our clinical trials program aims to provide access to innovative medicines for children and adolescents with cancer and hematologic conditions; and facilitate the clinical development of these from phase 1 to phase 3 and into clinical use.

Our group has a clear focus to develop targeted, immunotherapy and advanced therapy medicines (gene and cell therapy). Where needed, our group thrives to develop and contribute to academic clinical trials bringing novel therapies.

Clinical trials for patients with solid tumors and lymphoma

Leukemia clinical trials for children and adolescents with relapsed and refractory B and T acute lymphoblastic leukemia and acute myeloblstic leukemia.

Non-malignant Hematology clinical trials for the treatment of patients with hemolytic anemias such as sickle cell disease, piruvate kinase deficiency and PNH, bone marrow failure syndromes such as Fanconi anemia and for ultra-rare diseases such as atransferrinemia.

Clinical trials for hematopoietic stem cell transplantation (HSCT) conditioning and post HSCT complications such as acute and chronic graft versus host disease, thrombotic microangiopathy and infections.

CAR-T cell therapies for patients with acute lymphoblastic leukemia and lymphoma,

Advanced therapies for the treatment of post hematopoietic cell transplantation viral infections

In the field of non-oncological hematology, we have open trials to reduce the most frequent symptoms of sickie cell anemia with targeted therapies, as well as new therapies for pyruvate kinase deficiency or paroxysmal hemoglobinuria in children.

For pediatric patients affected by oncological diseases of the blood, we have new molecules for patients with acute lymphoblastic leukemia (including Ph+ALL) acute myeloblastic leukemia and chronic myeloid leukemia in a situation of refractoriness or relapse.

ONGOING COMPETITIVE PROJECTS:

• ETNA

• BEACON2

• ARI CAR-T trial (CDdH)

• ALADDIN

SELECTED PUBLICATIONS:

• Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study. J Clin Oncol. 2022 Jun 16:JCO2102981. doi: 10.1200/JCO.21.02981.

• Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. doi: 10.1200/JCO.20.02529. Epub 2020 Dec 17.

• Opportunities and Challenges in Drug Development for Pediatric Cancers. Cancer Discov. 2021 Mar;11(3):545-559. doi: 10.1158/2159-8290.CD-20-0779. Epub 2020 Dec 4.

• Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1566-1575. doi: 10.1016/S1470-2045(19)30617-5. Epub 2019 Sep 24.

• A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood. 2021 Mar 25;137(12):1582-1590. doi: 10.1182/blood.2020007848.

• Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study. Lancet Haematol. 2018 Oct;5(10):e450-e461. doi: 10.1016/S2352-3026(18)30153-4.

• Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer. Eur J Cancer. 2018 Sep;100:27-34. doi: 10.1016/j.ejca.2018.05.002. Epub 2018 Jun 21.

• Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Nat Med . 2019 Sep;25(9):1396-1401. doi: 10.1038/s41591-019-0550-z. Epub 2019 Sep 9.

PAST MEMBERS:

The success of our clinical trials unit has been possible thanks to the pioneering work by Soledad Gallego, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR and Josep Sanchez de Toledo, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR.