Acerca del VHIR
El Vall d'Hebron Instituto de Investigación (VHIR) promueve la investigación biomédica, la innovación y la docencia. Más de 1.800 personas buscan comprender las enfermedades hoy con el objetivo de mejorar su tratamiento mañana.
Investigación
Trabajamos para entender las enfermedades, saber cómo funcionan y crear mejores tratamientos para los pacientes. Conoce nuestros grupos y sus líneas de investigación.
Personas
Las personas son el centro del Vall d'Hebron Instituto de Investigación (VHIR). Por eso nos vinculamos con los principios de libertad de investigación, igualdad de género y actitud profesional que promueve la HRS4R.
Ensayos clínicos
Nuestra tarea no es solo básica o traslacional; somos líderes en investigación clínica. Entra para saber qué ensayos clínicos estamos llevando a cabo y por qué somos referente mundial en este campo.
Progreso
Queremos que la investigación que se efectúa en el Vall d'Hebron Instituto de Investigación (VHIR) sea un motor de transformación. ¿Cómo? Identificando nuevas vías y soluciones para fomentar la salud y el bienestar de las personas.
Core facilities
Ofrecemos un apoyo especializado a los investigadores tanto internos como externos, desde un servicio concreto hasta la elaboración de un proyecto en su totalidad. Todo ello, con una perspectiva de calidad y agilidad de respuesta.
Actualidad
Te damos una puerta de entrada para estar al día de todo lo que sucede en el Vall d'Hebron Instituto de Investigación (VHIR), desde las últimas noticias hasta las actividades e iniciativas solidarias futuras que estamos organizando.
El grupo de investigación se centra en encontrar nuevas dianas terapéuticas moleculares y biomarcadores basados en el conocimiento de la biología de los tumores pediátricos, las leucemias y las enfermedades hematológicas. La experiencia del grupo en los últimos años ha permitido identificar nuevas dianas moleculares muy cercanas a la fase clínica. En esta etapa, hemos consolidado colaboraciones con la industria biotecnológica para el desarrollo de pequeñas moléculas inhibidoras de procesos pro-oncogénicos como la invasión o la proliferación, con el objetivo de brindar a los pacientes terapias innovadoras y más específicas basadas en la evidencia biológica.
Otra línea de investigación se basa en el estudio de la biopsia líquida para desarrollar un sistema basado en NGS y monitorizar la probabilidad de recaídas.
Además, hemos implementado un programa de medicina personalizada para orientar el tratamiento de los pacientes en función de las alteraciones moleculares de sus tumores.
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.
IP: Lucas Moreno Martín-Retortillo
LABORATORY OF NEURAL TUMORS
Principal Investigator (Name, MD/PhD)
Miguel F. Segura
Research Team
Adrià Molero Valencuela, PhD Researcher
Ainara Magdaleno Cazón, Tehcnician
Ariadna Boloix Amenós, Postdoctoral Researcher
Carlos Jiménez Jiménez, Postdoctoral Researcher
María José Pérez García, Postdoctoral Researcher & Project Manager
Roberta Antonelli, Postdoctoral Researcher
Clinical Associated Researchers
Lucas Moreno, MD PhD. Expertise in drug development and clinical trials.
Anna Llort, MD PhD. Expertise in pediatric brain tumors
Constantino Sábado, MD. Expertise in Hepatoblastoma
Pediatric cancer has specific features that define it as an entity that in the majority of cases is certainly different than adult tumors; i.e. etiology, biology, response to treatment and prognosis are really different. The implementation of multimodal treatments (i.e. combinations of chemotherapies, radiotherapies, biological agents…) in the lasts 20 years has enabled the raise patient survival around 80%. Although the global survival of pediatric cancer is around 80%, patients with some types of tumors present a much lower survival. Moreover, almost two-thirds of patients who survive suffer severe side effects due to the treatment. Therefore, the development of therapies to treat 20% of patients who do not survive and to reduce toxicity of current treatments avoiding long-term side effects is extremely necessary.
Pediatric tumors of the nervous system are the most common solid malignant neoplasms of childhood cancer and the leading cause of cancer-related death in children. The main objective of my laboratory is to implement the use of epigenetic therapies, that is, therapies against gene expression modulators that, in turn, regulate several genes, pathways or cellular processes, without affecting the DNA sequence. The laboratory focus on neuroblastoma, a pediatric solid tumor of the peripheral nervous system, and on pediatric brain tumor of the central nervous system pediatric such as ependymoma, medulloblastoma or high-grade glioma among others.
The research strategy of the Neural Tumors Lab is based on the following research lines:
Development of RNA-based therapies for pediatric tumors
RNA-based therapies may represent a paradigm shift for the treatment of neuroblastoma, or cancer in general, because they have the potential to act on the entire transcriptome, thus expanding the number of drug targets, since they could modulate both RNA coding (2% of the total genome that is transcribed) and non-coding RNAs (80% of the genome that is transcribed). Within RNA-based therapies, the most advanced molecules from a clinical development point of view are small RNAs (e.g. siRNA or microRNA). Moreover, they will be safer therapies, since their mechanism of action will not induce permanent effects, especially in healthy cells. One of the working hypothesis of this line is that the microRNAs (miRNAs) deregulation is contributing to the metastatic and chemoresistant behavior of high-risk neuroblastoma and miRNA(s) levels restoration represents an attractive novel therapeutic approach.
Exploiting epigenetic vulnerabilities in metastatic neuroblastoma
Metastatic relapse is the major cause of death in neuroblastoma. 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. Our hypothesis is that metastatic cells can colonize distant organs thanks to the re-organization of their epigenetic landscape. Results of the last five years of the laboratory clearly shows that chromatin remodelers may play significant role in the aggressiveness of neuroblastoma. Therefore, in this cell line we are i) Characterizing the epigenetic landscape of metastatic neuroblastoma; ii) Characterizing the transcriptomic map of chromatin remodelers (i.e. SWI/SNF)-regulated genes in neuroblastoma metastasis; iii) Developing of an epigenetic therapy based on the inhibition of chromatin remodeling complexes; iv) Developing more sensitive tools to diagnose and target neuroblastoma metastasis.
Participation in drug development in pediatric solid tumors (e.g. Neuroblastoma, Hepatoblastoma, Brain Tumors)
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. Additionally, we are also pursuing the evaluation of the therapeutic potential of the KIF11 inhibitor 4SC-205 in pediatric tumors.
Identification of new treatments for pediatric brain tumors (i.e. Ependymoma)
Pediatric tumors of the central nervous system (CNS) are the most common solid malignancies in children, second only to hematologic malignancies, and are the leading cause of cancer-related deaths. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. One of the most advanced epigenetic therapies, only second to DNA methyl-transferase inhibitors, is the use of histone deacetylase inhibitors (HDACi). However, while shown to be effective in certain tumor types, their use in brain tumors did not yielded the expected results, probably because these drugs were not specifically designed to reach sealed tissues such as the brain. This research line constitutes a truly translational approach to further enhance the possibility of using HDACi in the treatment of brain tumors such as, but not restricted to, Ependymoma. Here, we are also elaborating a roadmap for the implementation of immunotherapies in pediatric brain tumors and characterizing the role of the tumor microenvironment in tumor growth and aggressiveness.
-Ref. PI20/00530 (AES ISCiii 2021-2023). PI: Miguel F. Segura. Nanotools for the treatment of metastatic neuroblastoma.
Summary: Metastatic relapse is the major cause of death in NB, where there remains a lack of therapies to target this stage of the disease. Therefore, understanding how NB cells invade, arrive at the metastatic niche and adapt to the new environment at the metastatic site, will help in designing more effective therapies to control the development and metastasis in NB. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that interfere with the translation of coding messenger RNAs (mRNAs) in a sequence-specific manner. In NB, over- or under-expression of specific miRNAs correlates with stage, progression (i.e. relapse / metastasis) and patient outcome. Particularly, miR-323a-5p was shown to be downregulated in NB metastasis and its restoration impaired tumor growth in vitro and in vivo.
MiRNA-based therapies face a major challenge, i.e. the limitations associated with their clinical administration, such as inefficient biodistribution and specific targeting of tissues. Conjugation of miRNA with nanostructured materials can improve targeting to specific tissues and reduce potential side-effects. The aim of this project is to test a new miRNA-based nanoformulation for the treatment of metastatic neuroblastoma.
Ref. DTS20/00018 (AES ISCiii 2021-2022). PI: Miguel F. Segura. Quatsomes as a novel nanomaterial platform for nucleic acids delivery.
Summary: RNA-based therapies against cancer have proved to show great potential since they are able to target all the transcriptome (coding and non-coding mRNAs), thereby expanding significantly the number of therapeutic targets.
The most therapeutically-advanced molecules in RNA-based therapies are microRNA (miRNA), endogenous noncoding small RNA that interfere with the translation and stability of RNA (coding and non-coding) in a sequence-specific manner. However, the application of these small molecules for treating human disease faces a major challenge, i.e. the limitations associated with their clinical administration such as inefficient biodistribution and specific targeting of tissues.
The aim of this project is to optimize our QS-miRNA nanoformulation for the treatment of high-risk neuroblastoma, an incurable pediatric tumor that demands new therapeutic approaches. Ours will consist on functionalizing QS-miRNA complexes with stealth polymers and specific targeting peptides which will reduce QSmiRNA complex aggregation, enhance blood circulation time and increase specificity towards neuroblastoma tumors.
Ref. ICI21/00076 (AES ISCiii 2022-2025). PI: Lucas Moreno. Scientific Officer: Miguel F. Segura. A phase I trial of ABTL0812 in paediatric patients with advanced cancer including neuroblastoma. Summary: 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 or sarcomas, or those with refractory or relapsed disease will not achieve a long-term cure. Most current therapies target cell division and proliferation by inducing DNA damage and programmed cell death. However, aggressive tumors often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumor cell death, particularly in combination, will provide new therapeutic opportunities for these patients. ABTL0812 is a first-in-class oral targeted anticancer compound that produces autophagy-mediated cytotoxicity selectively in cancer cells. It induces endoplasmic reticular stress (ER-stress) and blocks the AKT/mTOR pathway, resulting in cancer cell death. Our preclinical data indicate that ABTL0812 is effective in models of neuroblastoma (NB), even in cells that are resistant to multiple drugs. In NB, ABTL0812 further induces the associated unfolded protein response (UPR), which results in autophagy-dependent apoptosis and decreases the expression of MYCN, a key oncogenic driver of NB. Additionally, our preclinical studies suggest that ABTL0812 can potentiate the antitumor activity of chemotherapies and differentiating agents. In conclusion, ABTL0812 distinctive mechanism of action makes it standout to be used alone or in combination in high-risk neuroblastoma patients. Based on our group's preclinical work, ABTL0812 received orphan drug designation (ODD) by the FDA (15-4893) and EMA (EU/3/15/1485) agencies for neuroblastoma in 2015. ABTL0812 is currently in Phase II clinical development stage for adult tumors (pancreatic cancer) after successfully completing phase I, demonstrating safety and activity. This project arising from our group's preclinical work has the following aims: 1) to conduct a “first- in-child” clinical trial with ABTL0812, 2) to demonstrate the added value of combining ABTL0812 with immunotherapeutics and conventional chemotherapeutics3) to conduct an ambitious translational study to identify pharmacodynamic, predictive, prognostic and radiomic biomarkers. The clinical trial will evaluate ABTL0812 as single agent, in combination with irinotecan-temozolomide chemotherapy and with immunotherapy, i.e. anti-PD1, anti-GD2 or antiangiogenic therapies, to be decided based on preclinical work embedded into this project. The project addresses several objectives of the Strategic Action for Health of this call and priority actions of AES2021 such as development of new drugs for treatment of rare and severe diseases and drugs with ODD. Furthermore, this study is aligned with the neuroblastoma drug development strategy aimed at finding to target MYCN, one of the key drivers of aggressive pediatric tumors such as neuroblastoma.
SELECTED PUBLICATIONS (Top 10):
1.- 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.
2.- 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).
3.- 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).
4.- Muñoz-Guardiola P, Casas J, Megías-Roda E, Solé S, Perez-Montoyo H, Yeste-Velasco M, Erazo T, Diéguez-Martínez N, Espinosa-Gil S, Muñoz-Pinedo C, Yoldi G, Abad JL, Segura MF, Moran T, Romeo M, Bosch-Barrera J, Oaknin A, Alfón J, Domènech C, Fabriàs G, Velasco G, Lizcano JM. The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy. 2021 Jun;17(6):1349-1366. doi: 10.1080/15548627.2020.1761651. Epub 2020 May 25. PMID: 32397857; PMCID: PMC8204958.
5.- 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.
6.- 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.
7.- 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.
8.- 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.
9.- Jubierre L, Jiménez C, Rovira E, Soriano A, Sábado C, Gros L, Llort A, Hladun R, Roma J, Toledo JS, Gallego S, Segura MF. Targeting of epigenetic regulators in neuroblastoma. Exp Mol Med. 2018 Apr 27;50(4):51. doi: 10.1038/s12276-018-0077-2. PMID: 29700278; PMCID: PMC5938021.
10.- 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)
Nanomol Technologies S.L. (Barcelona, Spain)
Ability Pharma S.L. (Barcelona, Spain)
4SC (Münich, Germany)
PAST MEMBERS: (Name, actual position)
Dra. Luz Jubierre Zapater. Currently postdoctoral researcher at MSKCC, NY, USA.
Dra. Laia París-Coderch. Currently working as Validation and GMP Junior Consultant at TDV SL.
Dra. Aroa Soriano. Currently leading the Personalized Medicine Program at Vall Hebron Hospital.
Dr. Marc Masanas. Currently enrolled in a Master Program.
IP: Miguel Segura Ginard
RESEARCH LINE: RARE ANEMIA DISORDERS
Principal Investigator
María del Mar Mañú Pereira, PhD
Amira Idrizovic, MSc, PhD Researcher
Valeria Rizzuto, MSc, PhD Researcher
Anna Collado Gimbert, MD, Postgraduate Researcher
Victoria Gutierrez Valle, MSc, Postgraduate Researcher
María de los Ángeles Rodríguez, PhD, Project Manager
Claire Diot Lefebvre, MA, Project Manager
Rare anemia disorders (RADs) embrace a highly heterogeneous group of red blood cell and erythropoiesis defects characterized by presenting anemia of variable degree, from mild to life threatening chronic blood-transfusion dependence conditions. RADs include mainly sickle cell disorders (SCD), Thalassemia disorders, Rare constitutional hemolytic anemia due to a red cell membrane anomaly or to an enzyme disorder, Constitutional dyserythropoietic anemia and Constitutional anemia due to iron metabolism disorders.
Despite the rapid developments in genetic testing and the subsequent increased knowledge of molecular defects underlying RADs, disease pathophysiology and complex genotype-phenotype correlations are poorly understood and often unexplained. The recent availability of new therapeutic options for RADs makes even more crucial the development of innovative diagnostic strategies for patients’ genetic and phenotypic characterization for development of predictive scores and personalized medicine. Thus, novel diagnostic, exploratory and functional tests are needed in order to identify new disease mechanisms, to discover novel biomarkers, to improve disease classification, and to investigate differences in response to therapy.
Genetic and genome-wide association studies have found that two factors influence the SCD clinical expression: the ability of the patient to produce HbF and the co-existence with alpha-thalassemia but, it is unlikely they are the only ones. Through the new techniques of massive sequencing and association studies, genes with potentially effects to the pathogenesis of SCD or modulators of the phenotype disease have become candidates for study. These genetics modulators can be divided in; Primary: responsible of HbS polymerization and RBCs sickling and Secondary: modulators of sub phenotypes and complications of the disease. Predicting the phenotype of SCD in the first months of life, or even in the adult life, would allow a precise prognosis, individualized treatment and avoid unnecessary interventions. However, it is necessary to correlate these new variants with the physiological behavior of the RBCs and certain clinical manifestations allowing the definition of markers that prevent the appearance of acute events or predict the response to treatments.
The Lorrca® Maxsis is a unique instrument which combines RBC deformability by ektacytometry, osmoscan, oxygenscan and aggregometry; all temperature controlled. It is capable of fully automated measurement and calculation of various phenomena of RBC’s by analysis of their rheological behavior. The technique accurately detects deformability as a function of shear stress, as a function of oxygen tension (pO2) and aggregation of the RBCs respectively.
Additionally, the future of medicine aims to bioengineer devices to mimic human systems to predict efficiently for different patients (personalized medicine) in a fast way. They also may provide new approaches to develop novel dynamic disease models. A step forward in this field concerns "organ-on-chip" technologies. By integrating living cells cultures in microfluidic devices, the most relevant biological and mechanical properties of organic functional units can be reproduced.
However, as for other rare diseases, basic, translational and clinical research in RADs is hampered by the existing fragmentation or unavailability of comparable data at the EU level. A European approach for the standardised collection of data regarding the main clinical complications of RADs is fundamental to establish the need and the priorities in the development of research projects, clinical trials, guidelines and health policies that allow the better provision of healthcare to RADs patients.
Our research strategy is focused on the development and validation of innovative methodological approaches for better characterization of patients affected by RADs according to their individual features to allow personal risk profiles and personalized medicine.
Specific objectives include:
1) To investigate and / or validate genetic modifiers of RADs both new and previously described by GWAS as markers for prognosis and clinical course based on massive sequencing approaches.
2) To assess the RBC rheological properties by use of ektacytometer LoRRca and the two available modules: Osmoscan and Oxygenscan. The results will provide information of RADs patients risk profile and response to treatment.
3) In collaboration with IBEC, to model the progression of RADs in a spleen-like filtering unit using microfluidic technologies to develop a novel diagnostic device for prognosis and patients’ stratification. This device will be used for the characterization under flow of rheological and mechanical properties of single RBCs.
4) To develop AI-algorithms combining different –OMICs data (genomics, metabolomics) with other laboratory and clinical data for personalized medicine in RADs.
In parallel, we are one of the three coordinating hubs of the European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet), established in 2017 to contribute to innovative, efficient and sustainable health systems and facilitate access to better and safer healthcare for EU citizens while decreasing the cross-border health barriers existing for information and patient mobility in rare hematological diseases (RHDs).
On the specific area of the epidemiological surveillance, we are coordinating the establishment of the European Rare Blood Disorders Platform (ENROL), conceived in the core of ERN-EuroBloodNet and with the endorsement of European Hematology Association, as an umbrella for both new and already existing registries on RHDs. ENROL aims at avoiding fragmentation of data by promoting the standards for patient registries' interoperability released by the EU RD platform, combining the exhaustiveness of data collection at EU level for health planning and epidemiological porpoises, with a higher level of data granularity for identification of patients’ cohorts.
In this context, we are also coordinating the implementation of the Rare Anaemia Disorders European Epidemiological Platform (RADeep), contributing to ENROL on the field of RADs. RADeep was endorsed by ERN-EuroBloodNet for the standardized collection of data of patients affected by any RADs at the European level. RADeep is built in line with the EU RD Platform, and is open to any national registry and medical center willing to actively collaborate as data providers in EU, starting with a pilot in 7 European countries: Belgium, Denmark, France, Germany, Italy, Spain and Sweden.
ONGOING COMPETITIVE PROJECTS
ERN-EuroBloodNet – CHAFEA - EU4H-2022-ERN-IBA. ‘European Reference Network on Rare Hematological Disorders’. Coordinador: Pierre Fenaux (AP-HP, Paris). PI: María del Mar Mañú Pereira. Duration: March 2022 – September 2023.
Summary: The European Reference Network in Rare Hematological Disorders, ERN-EuroBloodNet, was officially established by the European Commission in March 2017 as one of the 24 ERNs in rare disorders. ERN-EuroBloodNet is conceived to contribute to innovative, efficient and sustainable health systems and facilitate access to better and safer healthcare for EU citizens while decreasing the cross-border health barriers existing for information, samples and patient mobility in Rare Hematological Diseases (RHD). www.eurobloodnet.eu
GA 964908 — ERICA — H2020-SC1-BHC-2018-2020. ‘European Rare dIsease research Coordination and support Action’. Coordinator: Franz Schaefer (University of Heidelberg, Germany). PI: María del Mar Mañú Pereira. Duration: March 2021 – February 2025
Summary: ERICA consortium aims to build on the strength of the 24 individual European Reference Networks (ERNs) in Rare Diseases and create a platform that integrates all ERN’s research and innovation capacity. Through knowledge sharing, engagement with stakeholders in the rare disease domain and assembly of transdisciplinary research groups working across the global health spectrum ERICA strives to reach the following goals: new intra- and inter-ERN rare disease competitive networks; effective data collection strategies; better patient involvement; enhanced quality and impact of clinical trials; increased awareness of ERN’s innovation potential; Through integration of ERN research activities, outreach to European research infrastructures to synergistically increase impact and innovation ERICA will strengthen the research and innovation capacity of the ERNs. This will result in safe, accessible and efficient access of therapies for the benefit of patients suffering from rare diseases and conditions.
GA 101017549 – GENOMED4ALL - H2020-SC1-FA-DTS-2020-1. ‘Genomics and Personalized Medicine for all though Artificial Intelligence in Haematological Diseases’. Coordinator: Federico Álvarez (Universidad Politécnica de Madrid, Spain). PI: María del Mar Mañú Pereira. Duration: January 2021 – December 2024
Summary: GENOMED4ALL will support the pooling of genomic, clinical data and other “-omics” health data through a secure and privacy respectful cross-border data sharing platform based on the novel Federated Learning scheme, to advance research in personalised medicine in haematological diseases thanks to novel AI models. GENOMED4ALL will make use of the existing infrastructures, including powerful High Performance Computing facilities, hospital registries, data processing tools, and pre-existing repositories, starting from 10 clinical partners repositories to be enlarged especially by the resources provided by ERN-EuroBloodNet where GENOMED4ALL clinical partners have a leading position. GENOMED4ALL will demonstrate the potential and benefits of trustable and explainable AI technologies, with a novel approach to AI models and algorithms to exploit the powerful set of "-omics" data which will be at researchers' disposal leading to more reliable and meaningful outcomes for advancing research and personalised medicine, with 3 use cases covering oncological and non-oncological Haematological Diseases, including: Myelodysplastic syndromes, Multiple Myeloma, and Sickle Cell Disease.
PI20/01454 – INTEGRA - AES – ISCiii. ‘Enabling personalized medicine of sickle cell disease patients based on integrative diagnosis of new generation methodologies’. PI: María del Mar Mañú Pereira. Duration: January 2021 – December 2023.
Summary: Sickle cell disease (SCD) is a rare life threating condition with an increasing health burden in Spain. Hematologic stem cells transplantation is the only curative treatment, usually indicated before the severity of the clinical picture is still unclear; meanwhile gene therapy is still on clinical research. New therapeutic options (i.e Crizanlizumab, Voxelotor) arise a new challenge in SCD; prognosis and personalized medicine become increasingly more important. INTEGRA aims to develop an integrative diagnostic approach based on deep phenotypic and genetic characterization through combining new generation methodologies. Red blood cells sickling behavior will be evaluated by the newly invented Oxygenscan ektacytometry to assess changes in parameters linked to SCD physiological and genetic modulators evaluated through GWAS approach. INTEGRA-SCD will translate into clinical practice the results of genomics, phenotypic characterization and clinical data combined in a single approach resulting on a reliable stratification of SCD patients for personalized medicine.
GA947670 – ENROL - CHAFEA — 3HP- HP-PJ-2019. ‘European Rare Blood Disorders Platform’. Coordinator: María del Mar Mañú Pereira. Duration: June 2020 – May 2023.
Summary: ENROL has been conceived in the core of ERN-EuroBloodNet as an umbrella for both new and already existing registries on rare hematological disorders (RHDs). ENROL aims at avoiding fragmentation of data by promoting the standards for patient registries’ interoperability released by the EU RD platform. ENROL’s principle is to maximize public benefit from data on RHDs opened-up through the platform with the only restriction needed to guarantee patient rights and confidentiality, in agreement with EU regulations for crossborder sharing of personal data. Accordingly, ENROL will map at the EU level demographics, survival rates, diagnosis methods, genetic information, main clinical manifestations and treatments in order to obtain epidemiological figures and identify trial cohorts for basic and clinical research. Moreover, it will allow promoting research especially for those issues that remain unanswered or sub optimally addressed by the scientific community and promoting clinical trials for new drugs. ENROL will enable the generation of evidence for better healthcare for RHD patients in EU as ultimate goal.
GA 860436 – EVIDENCE - H2020-MSCA-ITN-2019. ‘Erythrocytes Properties And Viability In Dependence Of Flow And Extra-Cellular Environment’. Coordinador: Lars Kaestner (Universität des Saarlandes, Germany). Principal Investigator: María del Mar Mañú Pereira. Duration: October 2019 – September 2023.
Summary: The objective of EVIDENCE is the exploration of the properties and behaviour of RBCs under flow conditions and in vivo to understand pathophysiology and to design novel diagnostic devices. Theoretical models will help to understand these RBC properties and will enable the transfer of the gained knowledge into diagnostic devises in general and into the development of a spleen-on-the-chip in particular. Furthermore, we aim to understand the effect of the flow in bioreactors, allowing the efficient production of RBCs in vitro with the goal to produce RBC for transfusion.
SELECTED PUBLICATIONS
Moraleda C, Aguilar R, Quintó L, Nhampossa T, Renom M, Nhabomba A, Ruperez M, Aponte JJ, Achtman AH, Mañú Pereira MDM, Schofield L, Alonso PL, Macete E, Menéndez C. Pathophysiology of Anemia in HIV-Infected Children Exposed to Malaria. Am J Trop Med Hyg. 2021 Jan 18;104(3):1003-1012
Rizzuto V, Mencattini A, Álvarez-González B, Di Giuseppe D, Martinelli E, Beneitez-Pastor D, Mañú-Pereira MDM, Lopez-Martinez MJ, Samitier J. Combining microfluidics with machine learning algorithms for RBC classification in rare hereditary hemolytic anemia. Sci Rep. 2021 Jun 30;11(1):13553.
Kountouris P, Stephanou C, Archer N, Bonifazi F, Giannuzzi V, Kuo KHM, Maggio A, Makani J, Mañú-Pereira MDM, Michailidou K, Nkya S, Nnodu OE, Trompeter S, Tshilolo L, Wonkam A, Zilfalil BA, Inusa BPD, Kleanthous M; on behalf of the International Hemoglobinopathy Research Network (INHERENT). The International Hemoglobinopathy Research Network (INHERENT): An international initiative to study the role of genetic modifiers in hemoglobinopathies. Am J Hematol. 2021 Nov 1;96(11):E416-E420.
Rizzuto V, Koopmann TT, Blanco-Álvarez A, Tazón-Vega B, Idrizovic A, Díaz de Heredia C, Del Orbe R, Pampliega MV, Velasco P, Beneitez D, Santen GWE, Waisfisz Q, Elting M, Smiers FJW, de Pagter AJ, Kerkhoffs J-LH, Harteveld CL and Mañú-Pereira MdM (2021) Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases. Front. Physiol. 2021 Volume 12.
Hanny Al-Samkari, M.D, Eduard J. van Beers, M.D., Ph.D, Kevin H.M. Kuo, M.D., Wilma Barcellini, M.D, Paola Bianchi, Ph.D, Andreas Glenthøj, M.D., Ph.D, María del Mar Mañú Pereira, Ph.D., Richard van Wijk, Ph.D., Bertil Glader, M.D., Ph.D, and Rachael F. Grace, M.D. The Manifestations of Disease in Pyruvate Kinase Deficiency: Report from the Pyruvate Kinase Deficiency Burden of Disease International Working Group. Haematologica 2020 Volume 105(9):2229-2239
Huisjes R, Makhro A, Llaudet-Planas E, Hertz L, Petkova-Kirova P, Verhagen LP, Pignatelli S, Rab MA, Schiffelers RM, Seiler E, van Solinge WW, Vives Corrons JL, Mañú-Pereira M, Kaestner L, Bogdanova A, van Wijk R. Density, heterogeneity and deformability of red cells as markers of clinical severity in hereditary spherocytosis. Haematologica. 2020 Jan 31;105(2):338-347
Bianchi P, Fermo E, Glader B, Kanno H, Agarwal A, Barcellini W, Eber S, Hoyer JD, Kuter DJ, Maia TM, Mañu-Pereira MDM, Kalfa TA, Pissard S, Segovia JC, van Beers, Gallagher PG, Rees DC, van Wijk R; with the endorsement of EuroBloodNet, the European Reference Network in Rare Hematological Diseases. Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency. Am J Hematol. 2019 Jan;94(1):149-161.
Llaudet-Planas E, Vives-Corrons JL, Rizzuto V, Gómez-Ramírez P, Sevilla Navarro J, Coll Sibina MT, García-Bernal M, Ruiz Llobet A, Badell I, Velasco-Puyó P, Dapena JL, Mañú-Pereira MM. Osmotic gradient ektacytometry: A valuable screening test for hereditary spherocytosis and other red blood cell membrane disorders. Int J Lab Hematol. 2018 Feb;40(1):94-102.
Mañú Pereira M, Ropero P, Loureiro C, Vives Corrons JL. Low affinity haemoglobinopathy (Hb Vigo) due to a new mutation of beta globin gene (c200 A>T; Lys>Ile). A cause of rare anaemia misdiagnosis. Am J Hematol. 2017 Jan 9.
Maria Garcia-Gomez, Andrea Calabria, Maria Garcia-Bravo, Fabrizio Benedicenti, Penelope Kosinski, Sergio López-Manzaneda, Collin Hill, María del Mar Mañú-Pereira, Miguel A. Martín, Israel Orman, Joan-Lluis Vives-Corrons, Charles Kung, Axel Schambach, Shengfang Jin, Juan A. Bueren, Eugenio Montini, Susana Navarro, Jose C. Segovia. “Safe and Efficient Gene Therapy for Pyruvate Kinase Deficiency”. Molecular Therapy 2016 Aug;24(7):1187-98
ACTIVE COLLABORATIONS WITH BIOTECH COMPANIES
Agios Pharmaceuticals, Inc (Cambridge, USA)
Novartis Pharma AG (Basel, Switzerland)
Celgene International II Sàrl (Couvet, Switzerland)
Novartis Farmacéutica S.A. (Barcelona, Spain)
IP: M Mar Mañu Pereira
Sarcoma Laboratory (Human Team)
Head of Sarcoma Laboratory
Josep Roma, PhD
Head of clinical service and scientific coordinator:
Lucas Moreno, MD, PhD
Post-doctoral Researchers
Gabriel Gallo-Oller, PhD
Pre-doctoral Researchers
Patricia Zarzosa
Natàlia Navarro
Guillem Pons
Julia Sansa
Lorena Valero
Technicians
Ainara Magdaleno
Research strategy and scope
Sarcomas originate in cells of mesodermal origin which, in normal conditions, end up forming some of the supporting tissues of the body, such as muscles, bones, tendons, fat, lymphatic vessels, blood vessels, nerves and joints. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, being the third most common extracranial solid tumour in children. This sarcoma accounts for approximately 5% of all malignant tumours in children and adolescents, with an annual incidence of 5.3 cases per million children under the age of 15. Approximately 65% ??of RMS cases are diagnosed in children under 6 years of age, with a lower incidence between 10 and 14 years of age and an increase in the number of cases in adolescents between 15 and 19. Currently, the survival rate of RMS has improved to around 70%. However, patients with metastatic RMS have 5-year disease-free survival as low as 30%. Therefore, mortality rates for RMS are still improvable, particularly in metastatic patients. For this reason, new therapeutic modalities are needed, especially for cases that still fail to respond adequately to conventional treatments and eventually die due to disease progression. Therefore, it is vital to strengthen research in this field, especially for cases refractory to conventional therapies.
Our research is focused on finding new molecular therapeutic targets and biomarkers based on knowledge of the biology of paediatric sarcomas. Our group has identified and continues to identify new molecular targets in soft tissue sarcomas (Notch, Hedgehog, miRNAs, pro-metastatic proteins, etc…) and the identification of biomarkers (tumour-specific cfDNAs in liquid biopsies). The experience of the group in recent years has permitted the identification of new potential targets that have entered the phase of drug development. In this stage, we have active collaborations with biotechnological industries in order to develop novel small molecules able to inhibit pro-oncogenic processes such as invasion and proliferation with the aim of providing patients with alternative and more specific biological evidence-based therapies. We are convinced that well-directed research not only has to spawn scientific publications but should also lead to the development of new therapeutic compounds or biomarkers that may directly benefit patients and the launch of new biotechnological products on the market.
Main competitive projects granted in the last years:
COMRDI15-1-0014 (ACCIÓ/FEDER) - IP: Josep Roma. AMMIC NEXTHEALTH COMMUNITY – Acceleradora de malalties minoritàries de Catalunya. From 2016 to 2019. Amount granted: 281,000€ (Total consortium 2.4M €).
Summary: This project consists of a network of high-technology companies and academic research centres, who act as an accelerator in the development of therapeutic solutions from early discovery to clinical stages. This integration of organisations will lead to more effective development of this type of solution and overcome difficulties and barriers of the environment thanks to collaboration, knowledge exchange and sharing of resources. This project is divided into two lines of research:
• New target development: Discovery and development of new therapeutic drugs and solutions for the treatment of rare diseases (such as paediatric cancer), from the stages of discovery of new molecules to the early stages of efficacy in the clinical setting.
• Personalised medicine and liquid biopsy: The development of genetic and epigenetic analysis tools as well as new screening platforms, which aid the research of the specific DNA alterations to be applied in the clinical setting for the benefit of pediatric cancer patients via selection of the best option for each patient (personalised medicine). This line of research includes also the follow-up of specific cell-free DNAs to evaluate the tumour burden in liquid biopsies with the aim of evaluating response to therapies and predicting relapses.
RTC-2017-6037 (Ministerio de ciencia e Innovación) – IP: Josep Roma. Desarrollo pre-clínico regulatorio de nuevos candidatos a fármacos oncológicos From 2018 to 2020. Amount granted: 60,000€.
El proyecto PRECLINONCO persigue como principal objetivo seleccionar entre 1 y 3 nuevos candidatos clínicos a fármaco oncológico de entre un grupo de aproximadamente 20 nuevas moléculas que ya han demostrado eficacia in vitro en las indicaciones tumorales sólidas de pulmón, páncreas y riñón en adultos, y en rabdomiosarcoma pediátrico. Para ello, será imprescindible explorar en profundidad su eficacia, toxicidad, farmacocinética, farmacodinamia y manufacturabilidad necesarios para priorizar las moléculas de partida y situar en el estadio preclínico regulatorio al candidato mejor posicionado.
CFP Kick cancer (ITCC2017) - IP: Soledad Gallego and Josep Roma. Pilot study to evaluate use of liquid biopsies in clinical and preclinical assessment of rhabdomyosarcoma disease burden. From 2018 to 2020. Amount granted: 180,000€.
Summary: There is an unmet clinical need to improve the assessment of disease burden and response to treatment in rhabdomyosarcoma to improve patient management and outcome. This pilot study aims to demonstrate the ability to detect and quantify cell-free tumour DNA in liquid biopsies from RMS patients.
For this purpose, tumour-specific mutations and translocation breakpoints are defined for each patient and analysed in blood samples via established and co-ordinated processes to permit patient follow-up. The main two goals of this project are:
Quantify circulating cell-free tumour cfDNA levels in plasma and in bone marrow. Results will be compared with clinical outcome and imaging results.
Compare results of plasma analyses in treated and untreated RMS mouse models, potentially capitalising on amplified tumour genes for preclinical monitoring.
Results are expected to justify sample collection and more extensive assessment in the next international clinical trial for Frontline and Relapse RMS (FaR-RMS) through the European paediatric and Soft tissue Study Group (EpSSG) in partnership with ITCC (Innovative Therapies for Children with Cancer).
PI18/00398 (AES ISCIII) - IP: Josep Roma. Innovative strategies for Hedgehog pathway inhibition as therapeutic target in rhabdomyosarcoma. From 2019 to 2021. Amount granted: 87,000€.
Summary: In this project we propose the study of some of the components of the Hedgehog pathway as a starting point for developing new molecular-specific therapies, with the strategy of inhibiting ligand binding with its classical Patched receptor and the much less studied Hedgehog co-receptors. The general philosophy of the project is to benefit from the knowledge generated from our previous basic research in order to translate it – with the indispensable help of the biotechnological Industry – into more effective therapies by attacking a pathway (Hedgehog) that plays a central role in rhabdomyosarcoma progression given its capability to activate proliferation and metastasis and, on the other hand, evade apoptosis. The proposed inhibition strategies and drugs are totally innovative, as there are no available therapies directed at these specific targets, which confers on them high potential as a complement to the current therapies.
54/032/201937 (Fundació La Marató de TV3) – IP and coordinator: Josep Roma. Liquid biopsy in pediatric sarcomas: deciphering the predictive potential of circulating tumor DNA and tumor-derived exosomes for early relapse detection. From 2021 to 2023. Amount granted: 300,000€
Summary: Sarcomas constitute a wide family of cancers, including rhabdomyosarcoma (RMS), non-RMS soft-tissue sarcomas, osteosarcoma and Ewing’s sarcoma. Despite their high degree of malignancy and given their high complexity and biological variability, sarcomas have historically been poorly studied compared to the most common cancers. Currently, only assessment by imaging techniques (NMR, PET, etc.) is accepted as sufficient evidence for starting a second-line therapy. The main limitation of these techniques is that they require a relatively large tumour size and knowledge of its location. No molecular methods that could be incorporated into clinical practice to advance the diagnosis of relapses in these diseases are currently available. Being able to do so in the future would be a breakthrough for patients who are not cured with first-line therapy. Thanks to the great progress made in massive sequencing in recent years, infinitesimal amounts of tumour-derived DNA circulating in blood (ctDNA) can be detected, and therefore, the presence of these fragments can be used as very early and sensitive biomarkers to allow very early detection of relapses. The same strategy can be attempted using exosomes, small structures released by cells that can travel through blood. If we are able to detect and measure specifically the exosomes emitted by tumours, we can assess whether a cancer is in progression long before image analysis can do so. Early detection of ctDNA and/or tumour-derived exosomes could trigger alarms some time before, thus allowing intensification of follow-up and even initiating a second-line treatment, with the obvious impact this may have on survival rates in the patients.
PI21/00640 (AES ISCIII) - IP: Josep Roma. Development of a new therapeutic target with high anti-oncogenic potential in childhood sarcomas: the pharmacological blockade of the Hedgehog co-receptor CDO. From 2022 to 2024. Amount granted: 120.000€
Summary: Survival rates in paediatric neoplasms have improved considerably in recent decades with an overall survival close to 80% in developed countries. However, some of the most common solid tumors, such as soft tissue or bone sarcomas, still show an adverse prognosis in a high percentage (close to 40%) of patients. Given the particularities of childhood cancers, identifying the molecules responsible for cancer progression may contribute to the advancement of new targeted therapies specially designed for these tumors. The present project stem from previous work by our group on the oncogenicity of the Hedgehog pathway in rhabdomyosarcoma (RMS) and explores one of its most interesting and innovative targets: the CDO co-receptor. After studying this co-receptor in recent years, we have been able to show that it is a target with exceptional anti-oncogenic potential. For this reason, we plan to deepen its study at the molecular level, address structural improvements of the inhibitor compound and assess its possible applicability to the treatment of childhood sarcomas with the generation of several animal models. The philosophy of the project is to start from basic biological knowledge to be able to translate it - with the indispensable help of the Biotechnology Company - into an improvement of future therapies by attacking a pathway that plays a central role in tumor progression in sarcomas, such as it is the Hedgehog pathway. The inhibition strategy proposed here has a high translational potential and is highly innovative, since there are no therapies directed against this specific target, not even in adult cancers.
PMP21/00073 (Ministerio de ciencia e innovación/NextGenerationEU - IP: Lucas Moreno. SEHOP-PENCIL study- Personalised medicine for Cancer in Children in Spain. From 2022 to 2026. Amount granted: 1.101.000€
Summary: Childhood cancer remains a challenge for our society with an unacceptable number of children dying from disease recurrence or suffering sequelae from intensive therapy. Incorporating high level Personalised Medicine (PerMed) 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.
10 selected publications on Paediatric Sarcomas:
1 - Dickkopf-1 Inhibition Reactivates Wnt/â-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo. Giralt I, Gallo-Oller G, Navarro N, Zarzosa P, Pons G, Magdaleno A, Segura MF, Sábado C, Hladun R, Arango D, Sánchez de Toledo J, Moreno L, Gallego S, Roma J. Int J Mol Sci. 2021;22(23):12921. PMID: 34884726.
2 - Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role. Giralt I, Gallo-Oller G, Navarro N, Zarzosa P, Pons G, Magdaleno A, Segura MF, Sánchez de Toledo J, Moreno L, Gallego S, Roma J. Pharmaceuticals. 2021;14(8):810. PMID: 34451907.
3 - Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance. Alcon C, Manzano-Muñoz A, Prada E, Mora J, Soriano A, Guillén G, Gallego S, Roma J, Samitier J, Villanueva A, Montero J. Cell Death Dis. 2020;15;11(8):634. PMID: 32801295.
4 - miRNA-7 and miRNA-324-5p regulate alpha9-Integrin expression and exert anti-oncogenic effects in rhabdomyosarcoma. Molist C, Navarro N, Giralt I, Zarzosa P, Gallo-Oller G, Pons G, Magdaleno A, Moreno L, Guillén G, Hladun R, Garrido M, Soriano A, Segura MF, Sánchez de Toledo J, Gallego S, Roma J. Cancer Lett. 2020;477:49-59. PMID: 32142919.
5 - Clonal dynamics in osteosarcoma defined by RGB marking. Gambera S, Abarrategi A, González-Camacho F, Morales-Molina Á, Roma J, Alfranca A, García-Castro J. Nat Commun. 2018;9(1):3994. PMID: 30266933.
6 - Ligand-dependent Hedgehog pathway activation in rhabdomyosarcoma: the oncogenic role of the ligands. Almazán-Moga A, Zarzosa P, Molist C, Velasco P, Pyczek J, Simon-Keller K, Giralt I, Vidal I, Navarro N, Segura MF, Soriano A, Navarro S, Tirado OM, Ferreres JC, Santamaria A, Rota R, Hahn H, Sánchez de Toledo J, Roma J, Gallego S. Br J Cancer. 2017;117(9):1314-1325. PMID: 28881358.
7 - Hedgehog pathway inhibition hampers sphere and holoclone formation in rhabdomyosarcoma. Almazán-Moga A, Zarzosa P, Vidal I, Molist C, Giralt I, Navarro N, Soriano A, Segura MF, Alfranca A, Garcia-Castro J, Sánchez de Toledo J, Roma J, Gallego S. Stem Cells Int. 2017;2017:7507380. PMID: 28243259.
8 - Embryonic Signaling Pathways as Potential Targets for the Treatment of Rhabdomyosarcoma (Editorial Thematic Issue). Gallego S, Roma J. Curr Drug Targets. 2016. Jul 29;17(11):1226-7. PMID: 26947582.
9 - Notch-mediated induction of N-cadherin and á9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells. Masià A, Almazán-Moga A, Velasco P, Reventós J, Torán N, Sánchez de Toledo J, Roma J, Gallego S. Br J Cancer. 2012;107(8):1374-83. PMID: 22976797.
10 - Notch pathway inhibition significantly reduces rhabdomyosarcoma invasiveness and mobility in vitro. Roma J, Masià A, Reventós J, Sánchez de Toledo J, Gallego S. Clin Cancer Res. 2011;17(3):505-13. PMID: 21177409.
Active collaborations with Biotech companies:
BCN peptides – Development of anti-metastatic compounds.
Leitat/Selabtec – Development of anti-cancer compounds.
QGenomics – Liquid biopsy development for detection of cfDNA in sarcomas.
Oncoheroes Biosciences – Development of anti-cancer compounds.
Flomics – Liquid biopsy for histiocytosis follow up.
IP: Josep Roma Castanyer
IP: M Mar Mañu Pereira Colaboradores: - Entidad financiadora: EUROPEAN COMMISSION Financiación: 221875 Referencia: HEMAFAIR/EC/WIDERA-2023-ACCESS-02-01/2023/MAÑU Duración: 01/07/2024 - 30/06/2027
IP: M Mar Mañu Pereira Colaboradores: Augusto Cesar Sao Aviles, Patricia González Ruiz, Claire Diot Entidad financiadora: EUROPEAN COMMISSION Financiación: 1543050.83 Referencia: ERDERA/EC/HLTH-2023-DISEASE-07-01/2023/MAÑU Duración: 01/09/2024 - 31/08/2031
IP: M Mar Mañu Pereira Colaboradores: Raquel Mosull del Campo Entidad financiadora: EUROPEAN COMMISSION Financiación: 1569581.5 Referencia: EUROBLOODNET-ERN_EU4H2023 Duración: 01/10/2023 - 30/09/2027
IP: Josep Roma Castanyer Colaboradores: - Entidad financiadora: VHIR Financiación: 296955 Referencia: VHIR-SEN-2023-002 Duración: 01/05/2024 - 30/04/2029
PMID: 38190578 Revista: JOURNAL OF CLINICAL ONCOLOGY Año: 2024 Referencia: J Clin Oncol. 2024 Jan 8:JCO2300458. doi: 10.1200/JCO.23.00458. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Barone, Giuseppe; Bautista, Francisco J; Burchill, Susan A; Caron, Hubert; Castel, Victoria; Castellano, Aurora; Chastagner, Pascal; Chesler, Louis; Corradini, Nadege; De Wilde, Bram et al. DOI: 10.1200/JCO.23.00458
PMID: 36941185 Revista: ANALES DE PEDIATRIA Año: 2023 Referencia: An Pediatr. 2023 Mar 18:S2341-2879(23)00053-4. doi: 10.1016/j.anpede.2022.03.009. Factor de impacto: Tipo de publicación: Carta o abstract Autores: Gros Subias, Luis; Morell Daniel, Mariona; Morey Olive, Miriam; Perez-Torres Lobato, Maria Rosario et al. DOI: 10.1016/j.anpede.2022.03.009
PMID: 36980521 Revista: Cancers Año: 2023 Referencia: Cancers (Basel). 2023 Mar 7;15(6):1636. doi: 10.3390/cancers15061636. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Gallego, Soledad; Gallo-Oller, Gabriel; Garcia-Gilabert, Lia; Magdaleno, Ainara; Moreno, Lucas; Navarro, Natalia; Pons, Guillem; Roma, Josep; Sanchez de Toledo, Josep; Sansa-Girona, Julia et al. DOI: 10.3390/cancers15061636
PMID: 37010353 Revista: PEDIATRIC BLOOD & CANCER Año: 2023 Referencia: Pediatr Blood Cancer. 2023 Jun;70(6):e30289. doi: 10.1002/pbc.30289. Epub 2023 Apr 3. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Alba, Amparo; Almaraz, Ricardo Lopez; Alvaro, Raquel Hladun; Alvaro, Raquel Hladun; Ash, Shifra; Baka, Margarita; Barco, Sebastiano; Brichard, Benedicte; Bugajska, Jolanta; Canete, Adela et al. DOI: 10.1002/pbc.30289
PMID: 37015036 Revista: JOURNAL OF CLINICAL ONCOLOGY Año: 2023 Referencia: J Clin Oncol. 2023 Jun 20;41(18):3408-3422. doi: 10.1200/JCO.22.02430. Epub 2023 Apr 4. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Bird, Nick; Buenger, Vickie; Casanova, Michela; Doz, Francois; DuBois, Steven G; Fox, Elizabeth; Glade Bender, Julia; Gore, Lia; Hawkins, Douglas S; Iasonos, Alexia et al. DOI: 10.1200/JCO.22.02430
PMID: NOPMID0100 Revista: Advances in Laboratory Medicine Año: 2022 Referencia: Adv Lab Med / Av en Med Lab. 2022;3(3):263-271. doi:10.1515/almed-2022-0016 Factor de impacto: Tipo de publicación: Artículo en revista nacional Autores: Barquin Del Pino , Raquel ; Benitez Carabante, Maria Isabel ; Casis Saenz, Ernesto; Castellote Bellés, Laura; Ferrer Costa, Roser; López Hellin, Joan; Martinez Sánchez, Luisa; Miarons Font , Marta; Paciucci Barzanti, Rosanna; Rodríguez Frias, Francisco et al. DOI: 10.1515/almed-2022-0016
PMID: 34865946 Revista: EUROPEAN JOURNAL OF CANCER Año: 2022 Referencia: Eur J Cancer. 2022 Jan;160:206-214. doi: 10.1016/j.ejca.2021.10.031. Epub 2021 Dec 2. Factor de impacto: 9.162 Tipo de publicación: Artículo en revista internacional Autores: Slater, Olga; Gains, Jennifer E; Kelsey, Anna M; De Corti, Federica; Zanetti, Ilaria; Coppadoro, Beatrice; Jorgensen, Mette; Gallego, Soledad; Orbach, Daniel H; Glosli, Heidi et al. DOI: 10.1016/j.ejca.2021.10.031
PMID: 34582098 Revista: PEDIATRIC BLOOD & CANCER Año: 2022 Referencia: Pediatr Blood Cancer. 2022 Feb;69(2):e29376. doi: 10.1002/pbc.29376. Epub 2021 Sep 28. Factor de impacto: 3.167 Tipo de publicación: Artículo en revista internacional Autores: Smeulders, Naima; Mudry, Peter; Zin, Angelica; Merks, Johannes H M; Slater, Olga; Alaggio, Rita; Gallego, Soledad; Coppadoro, Beatrice; Daragjati, Julia; Bisogno, Gianni et al. DOI: 10.1002/pbc.29376
PMID: 35130027 Revista: JOURNAL OF CLINICAL ONCOLOGY Año: 2022 Referencia: J Clin Oncol. 2022 Mar 20;40(9):1030-1032. doi: 10.1200/JCO.21.02612. Epub 2022 Feb 7. Factor de impacto: 44.544 Tipo de publicación: Carta o abstract Autores: Defachelles, Anne-Sophie; Bogart, Emilie; Casanova, Michela; Merks, Johannes H M; Bisogno, Gianni; Calareso, Giuseppina; Melcon, Soledad Gallego; Gatz, Susanne Andrea; Le Deley, Marie-Cecile; McHugh, Kieran et al. DOI: 10.1200/JCO.21.02612
PMID: 34294484 Revista: Año: 2021 Referencia: Nefrologia (Engl Ed). 2021 Jul 19:S0211-6995(21)00113-2. doi: 10.1016/j.nefro.2021.03.008. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Aguera, Maria Luisa; Beneyto, Isabel; Bernal, Gabriel; Calderari, Elena; Crespo, Marta; de Gracia, Maria Carmen; de Santiago, Carlos; Diaz, Candido; Diaz-Corte, Carmen; Dominguez-Gil, Beatriz et al. DOI: 10.1016/j.nefro.2021.03.008
PMID: 33713387 Revista: EUROPEAN JOURNAL OF HAEMATOLOGY Año: 2021 Referencia: Eur J Haematol. 2021 Jun;106(6):842-850. doi: 10.1111/ejh.13618. Epub 2021 Mar 30. Factor de impacto: 2.997 Tipo de publicación: Artículo en revista internacional Autores: Gonzalez Vicent, Marta, Diaz de Heredia, Cristina, Gonzalez de Pablo, Jesus, Molina, Blanca, Regueiro, Alexandra, Perez Martinez, Antonio, Palomo, Pilar, Lopez Corral, Lucia, Garcia, Estefania, Fernandez, Jose Maria et al. DOI: 10.1111/ejh.13618
PMID: 35071133 Revista: Frontiers in Pediatrics Año: 2021 Referencia: Front Pediatr. 2022 Jan 6;9:784377. doi: 10.3389/fped.2021.784377. eCollection 2021. Factor de impacto: 3.418 Tipo de publicación: Revisión en revista internacional Autores: Wolfl, Matthias, Qayed, Muna, Benitez Carabante, Maria Isabel, Sykora, Tomas, Bonig, Halvard, Lawitschka, Anita, Diaz-de-Heredia, Cristina et al. DOI: 10.3389/fped.2021.784377
PMID: 34884726 Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Año: 2021 Referencia: Int J Mol Sci. 2021 Nov 29;22(23). pii: ijms222312921. doi: 10.3390/ijms222312921. Factor de impacto: 5.924 Tipo de publicación: Artículo en revista internacional Autores: Magdaleno, Ainara, Giralt, Irina, Gallo-Oller, Gabriel, Navarro, Natalia, Zarzosa, Patricia, Pons, Guillem, Hladun, Raquel, Arango, Diego, Sanchez de Toledo, Jose, Moreno, Lucas et al. DOI: 10.3390/ijms222312921
PMID: 32278616 Revista: NEFROLOGIA Año: 2020 Referencia: Nefrologia (Engl Ed). 2020 May-Jun;40(3):265-271. doi: 10.1016/j.nefro.2020.03.002. Epub 2020 Apr 3. Factor de impacto: Tipo de publicación: Guía clínica Autores: Alonso, Angel; Alonso-Titos, Juana; Beneyto, Isabel; Cabello, Mercedes; Crespo, Marta; Diaz-Corte, Carmen; Franco, Antonio; Gonzalez-Roncero, Francisco; Guirado, Luis; Gutierrez, Elena et al. DOI: 10.1016/j.nefro.2020.03.002
PMID: 32837964 Revista: Anales de pediatria Año: 2020 Referencia: An Pediatr (Engl Ed). 2020 Aug;93(2):132-133. doi: 10.1016/j.anpede.2020.05.002. Epub 2020 Jul 1. Factor de impacto: Tipo de publicación: Otras (cartas al editor, abstracts, correcciones, etc.) Autores: Diaz de Heredia, Cristina; Moreno, Lucas; Riviere, Jacques G; Soler Palacin, Pere; Velasco Puyo, Pablo et al. DOI: 10.1016/j.anpede.2020.05.002
PMID: 33614543 Revista: Frontiers in Pediatrics Año: 2020 Referencia: Front Pediatr. 2021 Feb 5;8:614521. doi: 10.3389/fped.2020.614521. eCollection 2020. Factor de impacto: 2.634 Tipo de publicación: Artículo en revista internacional Autores: Esperanza-Cebollada, Elena, Vega-Garcia, Nerea, Perez-Jaume, Sara, Guerra-Garcia, Pilar, Perez-Martinez, Antonio, Garcia-Abos, Miriam, Robles Ortiz, Reyes, Pisa, Sandra, Adan, Rosa, Diaz de Heredia, Cristina et al. DOI: 10.3389/fped.2020.614521
PMID: 33564657 Revista: Biomedicine hub Año: 2020 Referencia: Biomed Hub. 2020 Jul 17;5(2):1-11. doi: 10.1159/000509272. eCollection 2020 May-Aug. Factor de impacto: 0 Tipo de publicación: Editorial en revista internacional Autores: Manu Pereira, Maria Del Mar, Gutierrez Valle, Victoria, Gutierrez Ibarluzea, Inaki, Kent, Alastair, Cattaneo, Ivana, Jagielska, Beata, Belina, Ivica, Tumiene, Birute, Ward, Adrian, Papaluca, Marisa et al. DOI: 10.1159/000509272
PMID: 31781490 Revista: Frontiers in Oncology Año: 2019 Referencia: Front Oncol. 2019 Nov 6;9:1173. doi: 10.3389/fonc.2019.01173. eCollection 2019. Factor de impacto: 4.137 Tipo de publicación: Revisión en revista internacional Autores: Boloix, Ariadna, Masanas, Marc, Jimenez, Carlos, Antonelli, Roberta, Soriano, Aroa, Roma, Josep, Sanchez de Toledo, Josep, Gallego, Soledad, Segura, Miguel F et al. DOI: 10.3389/fonc.2019.01173
PMID: 30606492 Revista: ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA Año: 2019 Referencia: Enferm Infecc Microbiol Clin. 2019 Mar;37(3):215-217. doi: 10.1016/j.eimc.2018.11.012. Epub 2018 Dec 31. Factor de impacto: 1.685 Tipo de publicación: Carta o abstract Autores: Barcelo, Maria Estrella, Navarro-Royo, Elisa, Melendo-Perez, Susana, Fenoy-Alejandre, Marina, Morey-Olive, Miriam, Soler-Palacin, Pere, Soler-Palacin, Pere, Melendo-Perez, Susana, Mendoza-Palomar, Natalia, Fernandez-Polo, Aurora et al. DOI: 10.1016/j.eimc.2018.11.012
PMID: 30586230 Revista: AMERICAN JOURNAL OF TRANSPLANTATION Año: 2019 Referencia: Am J Transplant. 2019 Jun;19(6):1798-1805. doi: 10.1111/ajt.15240. Epub 2019 Jan 25. Factor de impacto: 7.163 Tipo de publicación: Artículo en revista internacional Autores: Bader, P, Dalissier, A, Ifversen, M, Schulz, A, Gennery, A, Burkhardt, B, Badell Serra, I, Diaz-de-Heredia, C, Lanino, E, Lankester, A C et al. DOI: 10.1111/ajt.15240
PMID: 30485640 Revista: PEDIATRIC BLOOD & CANCER Año: 2019 Referencia: Pediatr Blood Cancer. 2019 Apr;66(4):e27562. doi: 10.1002/pbc.27562. Epub 2018 Nov 28. Factor de impacto: 2.486 Tipo de publicación: Carta o abstract Autores: Velasco, Pablo, Murillo, Laura, Dapena, Jose Luis, de Heredia, Cristina Diaz et al. DOI: 10.1002/pbc.27562
PMID: 28722800 Revista: BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY Año: 2018 Referencia: Basic Clin Pharmacol Toxicol. 2018 Jan;122(1):87-93. doi: 10.1111/bcpt.12851. Epub 2017 Aug 9. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Antonelli, Roberta; Avian, Alice; De Iudicibus, Sara; Decorti, Giuliana; Di Silvestre, Alessia; Lucafo, Marianna; Martelossi, Stefano; Naviglio, Samuele; Romano, Maurizio; Stocco, Gabriele et al. DOI: 10.1111/bcpt.12851
PMID: 29664914 Revista: PLoS One Año: 2018 Referencia: PLoS One. 2018 Apr 17;13(4):e0195176. doi: 10.1371/journal.pone.0195176. eCollection 2018. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Fernandez, Gerardo; Fuentes-Monteverde, Juan Carlos; Jimenez, Carlos; Llamas, Inmaculada; Reina, Jose Carlos; Rodriguez, Jaime; Torres, Marta et al. DOI: 10.1371/journal.pone.0195176
PMID: 30887009 Revista: HemaSphere Año: 2018 Referencia: Hemasphere. 2018 Oct;2(5):e146. doi: 10.1097/HS9.0000000000000146. Epub 2018 Oct 2. Factor de impacto: 0 Tipo de publicación: Artículo en revista internacional Autores: Petkova-Kirova, Polina, Hertz, Laura, Makhro, Asya, Danielczok, Jens, Huisjes, Rick, Llaudet-Planas, Esther, Manu-Pereira, Maria Del Mar, Vives Corrons, Joan-Luis, van Wijk, Richard, Bogdanova, Anna et al. DOI: 10.1097/HS9.0000000000000146
PMID: 29241729 Revista: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Año: 2018 Referencia: J Allergy Clin Immunol. 2018 Mar;141(3):1036-1049.e5. doi: 10.1016/j.jaci.2017.10.041. Epub 2017 Dec 11. Factor de impacto: 13.081 Tipo de publicación: Artículo en revista internacional Autores: Kiykim, Ayca, Barzaghi, Federica, Amaya Hernandez, Laura Cristina, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack, Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose et al. DOI: 10.1016/j.jaci.2017.10.041
PMID: 28160394 Revista: LIVER TRANSPLANTATION Año: 2017 Referencia: Liver Transpl. 2017 Apr;23(4):498-509. doi: 10.1002/lt.24738. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Cuervas-Mons, Valentin; D'Avola, Delia; Fabrega, Emilio; Fraga, Enrique; Gomez, Miguel-Angel; Herrero, Jose Ignacio; Jimenez, Carlos; Llado, Laura; Lopez, Pedro; Marti, Josep et al. DOI: 10.1002/lt.24738
PMID: 27777140 Revista: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Año: 2017 Referencia: Biol Blood Marrow Transplant. 2017 Jan;23(1):96-102. doi: 10.1016/j.bbmt.2016.10.014. Epub 2016 Oct 21. Factor de impacto: 4.704 Tipo de publicación: Artículo en revista internacional Autores: Rocha, Vanderson, Peters, Christina, Bader, Peter, Gluckman, Eliane, Dalle, Jean Hugues, Cornish, Jacqueline, Giardino, Stefano, Yakouben, Karima, Ruggeri, Annalisa, Volt, Fernanda et al. DOI: 10.1016/j.bbmt.2016.10.014
PMID: 28899930 Revista: EMBO Molecular Medicine Año: 2017 Referencia: EMBO Mol Med. 2017 Nov;9(11):1574-1588. doi: 10.15252/emmm.201707540. Factor de impacto: 9.249 Tipo de publicación: Artículo en revista internacional Autores: Diez, Begona, Genovese, Pietro, Roman-Rodriguez, Francisco J, Alvarez, Lara, Schiroli, Giulia, Ugalde, Laura, Rodriguez-Perales, Sandra, Sevilla, Julian, Diaz de Heredia, Cristina, Holmes, Michael C et al. DOI: 10.15252/emmm.201707540
PMID: 27894957 Revista: CANCER LETTERS Año: 2017 Referencia: Cancer Lett. 2017 Feb 1;386:196-207. doi: 10.1016/j.canlet.2016.11.020. Epub 2016 Nov 25. Factor de impacto: 5.992 Tipo de publicación: Artículo en revista internacional Autores: Sainz-Jaspeado, Miguel, Garcia-Monclus, Silvia, Lagares-Tena, Laura, Buj, Raquel, Hontecillas-Prieto, Lourdes, Sastre, Ana, Azorin, Daniel, Sanjuan, Xavier, Lopez-Alemany, Roser, Moran, Sebastian et al. DOI: 10.1016/j.canlet.2016.11.020
PMID: 27194325 Revista: JOURNAL OF NEUROSCIENCE Año: 2016 Referencia: J Neurosci. 2016 May 18;36(20):5437-47. doi: 10.1523/JNEUROSCI.3124-15.2016. Factor de impacto: Tipo de publicación: Artículo en revista internacional Autores: Ammassari-Teule, Martine; Antonelli, Roberta; Barberis, Andrea; Cherubini, Enrico; De Filippo, Roberto; Middei, Silvia; Pastore, Beatrice; Stancheva, Stefka; Zacchi, Paola et al. DOI: 10.1523/JNEUROSCI.3124-15.2016
PMID: 26489424 Revista: Clinical & Translational Oncology Año: 2016 Referencia: Clin Transl Oncol. 2016 Jul;18(7):708-13. doi: 10.1007/s12094-015-1421-9. Epub 2015 Oct 21. Factor de impacto: 2.075 Tipo de publicación: Artículo en revista internacional Autores: Guibelalde, M, Moreno, L, Munoz, A, Sastre, A, Acha, T, Bautista, F, Gallego, S, Canete, A, Mora, J, Diaz de Heredia, C et al. DOI: 10.1007/s12094-015-1421-9
PMID: 26323526 Revista: ANALES DE PEDIATRIA Año: 2016 Referencia: An Pediatr (Barc). 2016 Aug;85(2):109.e1-109.e6. doi: 10.1016/j.anpedi.2015.07.016. Epub 2015 Aug 29. Factor de impacto: 0.833 Tipo de publicación: Artículo en revista internacional Autores: Paris-Coderch, L, Soriano, A, Roma, J, Gallego, S, Sanchez de Toledo, J, Segura, M F, Boloix, A et al. DOI: 10.1016/j.anpedi.2015.07.016
PMID: 27038860 Revista: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Año: 2016 Referencia: Biol Blood Marrow Transplant. 2016 Jun;22(6):1073-9. doi: 10.1016/j.bbmt.2016.03.009. Epub 2016 Mar 30. Factor de impacto: 3.98 Tipo de publicación: Artículo en revista internacional Autores: Castillo, Nerea, Garcia-Cadenas, Irene, Diaz-Heredia, Cristina, Martino, Rodrigo, Barba, Pere, Ferra, Christelle, Canals, Carme, Elorza, Izaskun, Olive, Teresa, Badell, Isabel et al. DOI: 10.1016/j.bbmt.2016.03.009
PMID: 26052913 Revista: BONE MARROW TRANSPLANTATION Año: 2015 Referencia: Bone Marrow Transplant. 2015 Sep;50(9):1168-72. doi: 10.1038/bmt.2015.117. Epub 2015 Jun 8. Factor de impacto: 3.57 Tipo de publicación: Revisión en revista internacional Autores: Leblanc, T, Dufour, C, Dalle, J-H, Samarasinghe, S, Bonanomi, S, Corbacioglu, S, Wlodarski, M, Peffault de Latour, R, Peters, C, Gibson, B et al. DOI: 10.1038/bmt.2015.117
PMID: 24857430 Revista: Anales de Psicologia Año: 2015 Referencia: An Pediatr (Barc). 2015 Feb;82(2):62-7. doi: 10.1016/j.anpedi.2014.04.014. Epub 2014 May 22. Factor de impacto: 0.833 Tipo de publicación: Artículo en revista nacional Autores: Hladun, R, Badell, I, Gonzalez, M, Martinez, A M, Sanchez de Toledo, J, Olive, M T, Gonzalez, M E, Elorza, I, Diaz de Heredia, C et al. DOI: 10.1016/j.anpedi.2014.04.014
PMID: 26251675 Revista: Clinical Epigenetics Año: 2015 Referencia: Clin Epigenetics. 2015 Aug 6;7(1):82. doi: 10.1186/s13148-015-0107-z. eCollection 2015. Factor de impacto: 6.219 Tipo de publicación: Artículo en revista internacional Autores: Vella, Serena, Pomella, Silvia, Leoncini, Pier Paolo, Colletti, Marta, Conti, Beatrice, Marquez, Victor E, Strillacci, Antonio, Roma, Josep, Gallego, Soledad, Milano, Giuseppe M et al. DOI: 10.1186/s13148-015-0107-z
PMID: 25137037 Revista: INTERNATIONAL JOURNAL OF CANCER Año: 2015 Referencia: Int J Cancer. 2015 Apr 1;136(7):1579-88. doi: 10.1002/ijc.29144. Epub 2014 Sep 2. Factor de impacto: 5.085 Tipo de publicación: Artículo en revista internacional Autores: Harvey, Harry, Piskareva, Olga, Creevey, Laura, Alcock, Leah C, Buckley, Patrick G, O'Sullivan, Maureen J, Segura, Miguel F, Gallego, Soledad, Stallings, Raymond L, Bray, Isabella M et al. DOI: 10.1002/ijc.29144
PMID: 24790059 Revista: HAEMATOLOGICA Año: 2014 Referencia: Haematologica. 2014 May;99(5):811-20. doi: 10.3324/haematol.2013.099747. Factor de impacto: 5.868 Tipo de publicación: Artículo en revista internacional Autores: Hussein, Ayad Achmed, Kamani, Naynesh, Minkov, Milen, Locatelli, Franco, Rocha, Vanderson, Sedlacek, Petr, Smiers, Frans, Thuret, Isabelle, Yaniv, Isaac, Cavazzana, Marina et al. DOI: 10.3324/haematol.2013.099747
PMID: 23955634 Revista: BONE MARROW TRANSPL Año: 2014 Referencia: Bone Marrow Transplant. 2014 Jan;49(1):24-9. doi: 10.1038/bmt.2013.120. Epub 2013 Aug 19. Factor de impacto: 3.466 Tipo de publicación: Artículo en revista internacional Autores: O'Brien, T A, Cunha, R, Loiseau, P, Ruggeri, A, Sanz, G, Michel, G, Iori, A P, Socie, G, Arcese, W, Picardi, A et al. DOI: 10.1038/bmt.2013.120
PMID: 24972767 Revista: HAEMATOLOGICA Año: 2014 Referencia: Haematologica. 2014 Sep;99(9):1509-15. doi: 10.3324/haematol.2014.109280. Epub 2014 Jun 27. Factor de impacto: 5.868 Tipo de publicación: Artículo en revista internacional Autores: Ruggeri, Annalisa, Labopin, Myriam, Sormani, Maria Pia, Sanz, Guillermo, Sanz, Jaime, Volt, Fernanda, Michel, Gerard, Locatelli, Franco, Diaz De Heredia, Cristina, O'Brien, Tracey et al. DOI: 10.3324/haematol.2014.109280
PMID: 25155056 Revista: CYTOPATHOLOGY Año: 2014 Referencia: Cytometry A. 2014 Dec;85(12):1020-9. doi: 10.1002/cyto.a.22514. Epub 2014 Aug 22. Factor de impacto: 3.181 Tipo de publicación: Artículo en revista internacional Autores: Almazan-Moga, Ana, Roma, Josep, Molist, Carla, Vidal, Isaac, Jubierre, Luz, Soriano, Aroa, Segura, Miguel Francisco, Llort, Anna, Sanchez de Toledo, Josep, Gallego, Soledad et al. DOI: 10.1002/cyto.a.22514
PMID: 23926304 Revista: BLOOD Año: 2013 Referencia: Blood. 2013 Sep 19;122(12):2135-41. doi: 10.1182/blood-2013-03-491589. Epub 2013 Aug 7. Factor de impacto: 9.06 Tipo de publicación: Artículo en revista internacional Autores: Locatelli, Franco, Crotta, Alessandro, Ruggeri, Annalisa, Eapen, Mary, Wagner, John E, Macmillan, Margaret L, Zecca, Marco, Kurtzberg, Joanne, Bonfim, Carmem, Vora, Ajay et al. DOI: 10.1182/blood-2013-03-491589
PMID: 22835227 Revista: Actas dermo-sifiliograficas Año: 2013 Referencia: Actas Dermosifiliogr. 2013 Mar;104(2):133-40. doi: 10.1016/j.ad.2012.06.001. Epub 2012 Jul 24. Factor de impacto: 0 Tipo de publicación: Artículo en revista nacional Autores: Bassas, P, Hilari, H, Bodet, D, Serra, M, Kennedy, F E, Garcia-Patos, V et al. DOI: 10.1016/j.ad.2012.06.001
PMID: 23377538 Revista: PEDIATRIC RADIOLOGY Año: 2013 Referencia: Pediatr Radiol. 2013 Aug;43(8):1049-52. doi: 10.1007/s00247-013-2624-2. Epub 2013 Feb 2. Factor de impacto: 1.565 Tipo de publicación: Carta o abstract Autores: Delgado, Ignacio, Elorza Alvarez, Izaskun, Vazquez, Elida, Sanchez-Montanez, Angel, Margariti, Persefoni et al. DOI: 10.1007/s00247-013-2624-2
PMID: 23557135 Revista: PEDIATRIC DERMATOLOGY Año: 2013 Referencia: Pediatr Dermatol. 2013 Jul-Aug;30(4):484-9. doi: 10.1111/pde.12117. Epub 2013 Apr 5. Factor de impacto: 1.041 Tipo de publicación: Artículo en revista internacional Autores: Martinez Peinado, Carmen, Diaz de Heredia, Cristina, To-Figueras, Jordi, Arias-Santiago, Salvador, Nogueras, Paloma, Elorza, Izaskun, Badenas, Celia, Moreno, M Jose, Tercedor, Jesus, Herrero, Carmen et al. DOI: 10.1111/pde.12117
PMID: 22550422 Revista: Sarcoma Año: 2012 Referencia: Sarcoma. 2012;2012:695603. doi: 10.1155/2012/695603. Epub 2012 Mar 11. Factor de impacto: 2.16 Tipo de publicación: Carta o abstract Autores: Gallego, Soledad, Sanchez de Toledo, Josep, Almazan-Moga, Anna, Roma, Josep et al. DOI: 10.1155/2012/695603
PMID: 22976797 Revista: BRITISH JOURNAL OF CANCER Año: 2012 Referencia: Br J Cancer. 2012 Oct 9;107(8):1374-83. doi: 10.1038/bjc.2012.411. Epub 2012 Sep 13. Factor de impacto: 5.042 Tipo de publicación: Artículo en revista internacional Autores: Sanchez de Toledo, J, Roma, J, Gallego, S, Toran, N, Reventos, J, Almazan-Moga, A, Masia, A, Velasco, P et al. DOI: 10.1038/bjc.2012.411
PMID: 22308292 Revista: BLOOD Año: 2012 Referencia: Blood. 2012 Mar 22;119(12):2949-55. Epub 2012 Feb 3. Factor de impacto: 9.898 Tipo de publicación: Artículo en revista internacional Autores: Auiti, A, Diaz de Heredia, Cristina, Wall, Donna, Bertrand, Yves, Veys, Paul, Slatter, Mary, Schulz, Ansgar, Chan, Ka Wah, Grimley, Michael, Ayas, Mouhab et al. DOI: 10.1182/blood-2011-06-363572
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Doctorando: Ariadna Boloix Amenós, Ariadna Boloix Amenós Director/es: Miguel Segura Ginard Universidad: Universidad Autònoma de Barcelona Año: 2019
Doctorando: Luz Jubierre Zapater Director/es: Miguel Segura Ginard, Soledad Gallego Melcón Universidad: Universidad Autònoma de Barcelona Año: 2017
Doctorando: Ana Almazan Moga Director/es: Soledad Gallego Melcón, Josep Roma Castanyer Universidad: Universidad Autònoma de Barcelona Año: 2016
Doctorando: Elena Andretta Director/es: Diego Arango Corro Universidad: Universidad Autònoma de Barcelona Año: 2015
La prestigiosa revista The Lancet publica los resultados de este estudio, fruto de más de 20 años de investigación preclínica y el seguimiento de los pacientes durante 7 años.
Durante el encuentro se destacó el papel del Hub de Investigación Pediátrica de Vall d’Hebron para impulsar la investigación en ninos, niñas y adolescentes.
El encuentro ha sido una oportunidad para conocer proyectos de ambas instituciones y promover la interacción entre los profesionales.